phosphatase and tensin homolog ( pten ) is a ubiquitously expressed protein that functions as a phosphatase to dephosphorylate phosphatidylinositol ( 3,4,5)-trisphosphate ( ptdins(3,4,5)p3 or pip3 ) by catalyzing the dephosphorylation of the 3 phosphate of the inositol ring in pip3 .
the resulting product of this reaction is the biphosphate product pip2 ( ptdins(4,5)p2 ) . since pip3 is a primary activator of the signaling intermediate akt , dephosphorylation of pip3 by pten results in inhibition of the akt signaling pathway .
akt is a serine / threonine - specific protein kinase that is critical for many cellular functions including cell proliferation , apoptosis , transcription , and cell migration and structure .
pten also functions as a protein phosphatase by dephosphorylating proteins including focal adhesion kinase in the cytosol and erk , histone h1 , rad51 , and cenc - p in the nucleus . therefore , pten has effects on cell migration via integrin signaling , chromatin remodeling through its interactions with histones , cell cycle progression and arrest independent of akt signaling , dna repair via its modulation of rad51 , and centrosome stability via its role with cenc - p .
pten 's structure , described in figure 1 , consists of a phosphatase domain harboring the active site and enzymatic function of the protein and a c2 domain responsible for the phospholipid membrane binding site . as such
, the c2 domain is responsible for cellular location and allows pten localization to membrane - bound pip3 ; this promotes pten 's phosphoinositide phosphatase function by locating it to the cellular location of its substrates .
the functions of the c - terminal and pdz domains are less defined . because the downstream signaling pathways that pten effects modulate very diverse and dynamic cellular functions , pten is responsible for regulating the signals of an abundance of mediators including cytokines , growth factors , integrins , and autacoid ligands of g - protein - coupled receptors [ 35 ] .
the cellular mechanistic effects of pten function and intrinsic akt inhibition include modulation of many pathways ; this includes cell cycle progression via p27 , wee1 , p21 , and cyclin d ; mtor - mediated cellular signaling ; apoptosis and survival effects mediated by bim , mdm2-p53 , bcl-2 , and bax ; cellular structure regulation mediated by laminins and cytoskeletal protein expression ; glycogen and glucose regulation and glycolysis by glycogen synthase , 6-phosphofructo-2-kinase , and as160 .
adding to the broad activity of pten are the numerous examples of signaling crosstalk with other transduction pathways including the erk , p38 , and jnk mitogen - activated protein kinases , the tgf and bmp - associated smad pathways , the cytokine - mediated jak - stat pathway , and ip3-mediated calcium signaling .
additionally , interesting recent findings have demonstrated that pten modulates the dna damage response and repair via its inhibition of akt . because of this diversity , any mediators that modulate pten expression levels or function have substantial effects on cellular function . as a critical cellular protein that modulates numerous processes
, it is expected that pten plays a major role in regulating proper development . yet , pten is still primarily known as a tumor suppressor  the loss of function of which leads to tumorigenesis . while this may be true ,
the last decade has seen a greatly enhanced understanding of how pten is regulated , particularly as this relates normal growth and development .
this review takes a critical look at the literature focusing on pten regulation , the effects of this regulation during mammalian development , and how it is regulated by classical developmental signal transduction mechanisms .
it is expressed as early as the embryonic stem cell stage , being detectable in embryonic day 3.5 blastocysts in both extraembryonic and embryonic tissues .
pten is required for critical hallmarks of developmental biology including cell proliferation , growth , death , and migration . in many tissues
, pten expression coincides with the need to repress or induce proliferation or differentiation in cells , depending on the tissue need in each location and time point . at an organismal level
, pten plays several critical roles in the early control of the patterning of embryos .
first , pten regulation of cell migration is known to control specification of the anterior - posterior axis of mouse embryos .
embryos that lack pten expression exhibit a notable set of morphological defects including the failure to correctly specify the anterior - posterior body axis , improper separation of body foci , and decreased coordinated migration of cells along the body axis .
pten is highly expressed from the midblastula transition through completion of gastrulation and embryonic layer separation . in this process
embryos lacking pten fail to exhibit proper patterning from the blastula into the germ layers .
, pten localization can be found throughout ectodermal , endodermal , and mesodermal - derived tissue , including the developmental precursors of the central nervous system and skin , the liver and gastrointestinal tract , the urogenital sinus , heart , and skeletal muscle [ 19 , 20 ] . anatomy of pten systems effects highlighed in figure 2 . following the separation of the germ layers ,
the high prevalence of germline pten mutations in cowden disease and bannayan - riley - ruvalcaba syndrome , lhermitte - duclos syndrome , autism spectrum disorders , and cns axon regeneration demonstrates the significance of pten in central nervous system development and physiology .
the brain has been the most extensively studied organ in the area of pten 's role in developmental biology , primarily because of its known role in the development of gliomas and medulloblastomas .
identified syndromes associated with germline pten in the cns include lhermitte - duclos disease , dysplastic gangliocytoma , gray matter heterotopias , mental retardation , autism , and seizures .
cell type - specific mutations of pten in animal models demonstrate developmental phenotypes and resulting pathology .
glial cell conditional null mutation of the pten gene promotes seizures and ataxia early in life in mice and promotes premature death .
brain size in these mice increases progressively over time relative to wild - type littermates , and these mutants develop hydrocephalus and untoward lateral ventricle growth .
these animals exhibit neural dysplasia , thickened internal granule cell layers , and a progressive increase in neuronal soma size .
further , mice with oligodendrocyte - specific pten deletion exhibit disruption in the myelination of axons .
importantly , these murine effects are similar to many common features associated with pten mutations in the human cns .
neuronal - specific pten deletion promotes soma hypertrophy , macroencephaly , and increased axonal outgrowth .
this latest finding has led to the hypothesis that pten inhibition may be a potential therapeutic mechanism for inducing axonal outgrowth in spinal injury patients .
these mice also exhibit increased dendritic spine density , increased caliber of neuronal projections , and alterations in synaptic transmission .
neurons from these mice exhibit disruption in bergmann - glia connections and disorganized cerebellar architecture .
neuronal - conditional pten null mice also display hyperactivity , signs of anxiety , heightened response to excitatory stimuli , and disrupted social interaction .
findings from these studies have prompted the hypothesis that pten expression anomalies may be at least in part responsible for cns - related disorders in humans .
pten - mediated signaling has long been known to be critical for the cytoprotection of both epithelial cells and melanocytes in the skin .
interestingly , pten has recently been shown to be responsible for regulating the events and timing of epidermal development .
this may have been predictable given the incidence of benign tumors of the skin in cowden 's syndrome , a known pten - driven condition .
conditional pten deletion induces hyperplasia of squamous cells resulting in mounted skin dermis and papillomas .
pten is necessary for proper development , lineage fate , and cell function in t cells , b cells , myeloid cells , nkt cells , and hematopoietic stem cells ( hscs ) , as demonstrated by several elegant studies involving global heterozygous and cell - conditional null pten models [ 3540 ] .
it has been known that pten ( + / ) mice exhibit lymphoid hyperplasia progressing to t - cell lymphoma complete with large nodal masses , and it has now also been reported that pten ( + / ) mice develop autoimmune disorders at an early age due to abrogated pten function .
cell - type t - cell conditional pten null mice exhibit lymphadenopathy , splenomegaly , and hyperplastic enlarged thymus . similar to the global pten heterozygous mice , conditional nulls also exhibit autoreactivity evidenced by increased levels of autoantibodies , expanded t - cell proliferation , and increased cytokine synthesis and release .
indirect studies show that pten - mediated signaling plays a role in natural killer ( nk ) cells .
unfortunately , true cell - selective knockout of pten in natural killer ( nk ) cells has not been reported due to the lack of a cell - type specific promoter . however , purified nk cells from pten immune - system null mice exhibit abrogated maturation and activation .
studies have demonstrated that when these cells were adoptively transferred into nk null mice harboring metastatic melanoma cells , the null cells exhibit strongly decreased protection from metastases relative to wild - type nkt cells [ 39 , 40 ] .
these results demonstrate that one critical role of nk cells , namely , tumor targeting , is attenuated in pten null nk cells .
in addition , b - cell lineage - specific pten null mice exhibit expanded splenocytes , mesenteric lymph node cells , and peritoneal cells .
b cells deficient in pten display enhanced proliferation upon epitope or mitogen stimulation , and defective class - switch antibody recombination resulting in decreased production of iga and igg antibodies and elevated igm production .
neutrophils isolated from mice with pten - null myeloid lineage cells display increased actin polymerization with enhanced membrane ruffling , pseudopodia formation , chemotaxis , and migratory speed .
paradoxically , these mice are more susceptible to infection with leishmania and exhibit a slower clearance of infection than wild - type littermates .
this disconnect appears to be due to decreased secretion of tumor necrosis factor ( tnf ) by mutant macrophages in these mice . to date , little else is known about the development of monocytes in myeloid - specific pten null bearing animals .
deletion of pten in murine hematopoietic stem cells in mice results in a very rapid onset of myeloproliferative disorders and an eventual depletion of the stem cell pool , which , despite their proliferative nature , results in the loss of the ability of these stem cells to produce all lineages needed for proper immune functioning .
these myeloproliferative disorders progressed to acute myeloid leukemia or acute lymphoblastic leukemia . in a demonstration
that akt - signaling is downstream of this phenotype , increased hsc proliferation and even the development of myeloproliferative disorders and leukemia are all rescued when the mice were treated with rapamycin .
there are numerous studies to date examining the developmental effects of organ - specific pten mutation in mouse models .
mammary ducts in tissue - specific conditional pten null mice exhibit loss of differentiation , enhanced growth , excessive side branching , and precocious budding relative to wild - type controls .
these phenotypes are reported during puberty but also manifest their effects during mammary expansion during pregnancy .
pten is important for the normal physiology of oocytes , as pten deficiency in murine oocytes causes the entire oocyte pool to become activated prematurely .
this proves to be critical for fertility and reproduction , as premature oocyte activation resulted in females having a maximum of one normal - sized litter before they became infertile at 12 - 13 weeks of age .
fabpcre-(ptenflox / flox ) mice exhibit a number of interesting phenotypes in the genitourinary system .
pten deletion occurs in the bladder , ureter , kidney , colon , prostate , seminal vesicles , and vagina of these mutants .
as expected , deletion of pten resulted in increased susceptibility to chemically induced carcinogenesis . similarly , epithelial hyperplasia is present in organ specific pten knockouts , followed by intraepithelial neoplasia and ultimately by invasion of the cancer cells as invasive adenocarcinoma [ 4951 ] .
embryonic deletion of pten in the lower urinary system results in a loss of proper differentiation within affected cells , ultimately resulting in loss of proper patterning and growth control . based on these data and the collection of phenotypes observed in pten deleted cells and animals ,
it is likely that a loss of differentiation of cells plays a master role in pten 's role in organ development .
recent reports have demonstrated a critical role for pten in the branching morphogenesis and nephron patterning of developing kidneys .
pten has been shown to be indispensable for developing bud outgrowth , mesenchymal invasion , and branching morphogenesis in developing kidneys by mediating the signaling downstream of gdnf / ret receptor tyrosine kinases . again , this involves differentiation and chemotaxis of epithelial cells .
more recently , lindstrm et al . have shown that pten sits at the center of nephron development by integrating signaling from bmp and wnt - beta - catenin pathways .
disruption of pten results in a loss of coordinated signaling and a loss of proper patterning of epithelial cells along the axis of the nephron tubule .
numerous developmental effects of pten have been noted in the gastrointestinal tract . in the colon ,
pten ( + / ) mice develop hamartomatous polyps consistent with disrupted control of differentiation of cells .
further , pten is critical for colon homeostasis involving inflammatory repair and recovery , processes that reactivate developmental signaling mechanisms . in the liver , loss of pten
in addition , hepatomegaly is observed in mice with conditional hepatic pten knockout , as the ratio of liver weight to body weight increased in the mutants when compared with wild - type controls .
livers harvested from mutant animals are discolored and show accumulation of triglycerides consistent with steatohepatitis associated with severe inflammation .
passive diffusion of fatty acids in hepatocytes was enhanced in pten null mice , and pten - deficient hepatocytes exhibit an increased rate of fatty acid synthesis via induced fatty acid synthase .
pten - deficient mice exhibit defects in glucose metabolism , including decreased fasting plasma glucose levels and reduced serum insulin levels .
clearance of glucose was accelerated in the absence of pten concurrent with increased liver glycogen storage .
pancreatic islet beta - cell specific pten - deficient mice exhibit increases in islet cell numbers , total islet mass , and an increase in -cell progenitor proliferation during embryonic development and early postnatal life .
. these mice are significantly smaller than controls and have a shorter lifespan . in some studies ,
severe hypoglycemia is associated with seizure activity and premature death before 5 weeks of age .
in addition pten ( + / ) mice exhibit protection against increased insulin production during reactive oxygen species - dependent type two diabetes and insulin - resistance upon aging .
pten 's role in maintaining glucose balance is not limited to the liver and pancreas but also involves adipocytes and myocytes .
inactivation of pten specifically in adipocytes produces no obvious gross morphological effects on the adipose tissue or adipose tissue mass .
however , this mouse exhibits increased systemic glucose tolerance and insulin sensitivity complete with decreased fasting insulin and resistin levels . by controlling serum insulin and resistin levels
similarly , skeletal and cardiac muscle cell - specific deletion causes increased systemic glucose tolerance and insulin sensitivity .
interestingly , however , pten loss in these tissues seems to protect these mice from streptozotocin - induced diabetes and hyperglycemia indicating that the insulin hypersensitivity exhibited in tissue - selective pten - deficient mice allowed them to maintain proper glucose levels .
specific lung deletion of pten during embryogenesis results in impaired lung morphogenesis and early postnatal death .
the lungs of these neonates exhibit increased epithelial cell proliferation and decreased alveolar cell differentiation .
further study of pten 's role in lung development revealed that pten - regulated signaling mediates lung endodermal morphogenesis coordinate with the overall developmental process in the lung , and it is central to the interaction of several signaling pathways including the tgf beta - smad and nkx2.1 pathways .
pten knockout in endothelial and endocardial cells in mice results in embryonic lethality due to increased capillaries and endothelial cell hypertrophy .
these mutant embryos exhibit pericardial cavity enlargement , leakage of blood into the pericardial cavity , and enlarged trunk vessels secondary to pericyte and vascular smooth muscle cell recruitment to blood vessels .
in addition , cardiomyocyte - specific deletion of pten leads to cardiac phenotypes via development of cardiac hypertrophy and contractile defect .
future studies on pten will hopefully be targeted at assessing injury - related responses in the cardiovascular system , as deletion of pten in cardiomyocytes has been shown to protect the heart from maladaptive remodeling upon biomechanical stress .
mice with deletion of pten in osteochondroprogenitor cells exhibit growth plate dysfunction and overgrowth of the vertebrae
. the bodies of these mice are notably longer than wild - type controls , demonstrating a critical defect that results in loss of proper skeletal development .
interestingly , this increase in length was not due to bone cell proliferation increases as might have been expected but rather is due to increased matrix deposition and cellular hypertrophy . in a second model , osteoblast - specific knockdown of pten expression results in increased bone volume and density .
while pten remains virtually synonymous with cancer biology , the studies presented here make the importance of proper pten signaling for regulating a wide variety of developmental processes clearly evident . from regulation of growth , differentiation , glucose maintenance , and repair and recovery to gross effects on organ and systems development ,
pten is a protein with vast consequence in the field of developmental biology , and the signaling affected by its expression is expansive .
further , pten 's effects on development acquire greater importance when the role that developmental signaling plays in cancer growth and progression is considered .
therefore , an extensive knowledge of how pten is regulated by developmental signaling , apart from somatic or genetic mutation , is required for complete understanding of pten 's role in these important physiological processes .
most studies evaluating the role of pten in human diseases have been centered upon mutation in pten itself , and most of this work is done in its relationship to cancer initiation and progression .
there is no question that mutations of pten play a critical role in this regard .
studies over the last decade , however , have discovered a tremendous diversity in the regulation of pten expression and found that pten is tightly controlled both transcriptionally and posttranscriptionally .
recent studies to date have implicated micrornas in pten suppression , and the enzymatic phosphatase activity of pten is also regulated posttranslationally via phosphorylation , ubiquitination , or oxidation [ 69 , 70 ] .
this section highlights the multifaceted mechanisms of pten regulation , supported by the rapidly expanding literature on pten 's role in growth and patterning of tissues during development .
in addition , special emphasis is given to mediators and pathways involved in development including insulin - like growth factor , transforming growth factor , bone morphogenetic proteins , notch , forkhead transcription factors ( fox ) , and others .
pten 's complex regulation at the levels of transcription , mrna stability , posttranslational modifications , and mirna levels has become a critical series of mechanisms deserving a comprehensive review ( for an overview , see figure 3 ) .
the regulation of pten expression occurs at transcriptional , posttranscriptional , posttranslational , and protein - protein interaction levels .
we highlight developmental pathways involved in regulating pten expression at all these regulation points and make special reference to connections between signal transduction and development .
one critical aspect of pten 's regulation during development begins at the transcriptional level . to date
, pten expression has been found to be regulated at the transcriptional level by pathways involving p53 , ppar , egr-1 , nf-b , and smads , and this regulation affects the development of proper immune function , the vasculature , the nervous system , the gastrointestinal system , and the airways [ 63 , 72 , 73 ] . while pten is constitutively expressed in many normal adult tissues ,
pten expression is altered dramatically through the course of development and in pathological settings , and a primary source of this regulation comes from bona fide developmental regulators .
in addition , suppressors of cytokine signaling ( socs ) and snail also induce pten and act by countering the growth - promoting actions of cytokines and growth factors in development and repair and recovery . this mechanism has been clearly demonstrated in axonal outgrowth during neuron development and regeneration .
while the physiological ramifications of this regulation remain unsolved , mediators that slow or inhibit cell proliferation are often involved in inducing this protein .
developmental mediators including notch , transforming growth factor beta ( tgf ) , bone morphogenetic proteins ( bmps ) , and hedgehogs ( hhs ) all participate as players in external pten regulation [ 7578 ] , regulating such processes as proliferation and targeted epithelial budding and outgrowth of visceral organs [ 76 , 77 ] , and outgrowth in neurons . as the direction of cell growth and differentiation
balances on the fulcrum between the proliferative and differentiating actions of these mediators , their regulation to induce or repress pten expression is a critical aspect of their actions during development .
the critical developmental mediator tgf contains both growth promoting and inhibiting differentiation qualities , and tgf induces pten during differentiation when growth is slowed and inhibits its expression during proliferation .
in addition , the developmental regulator dj-1 was recently identified as a novel negative regulator of pten by a genetic screen in drosophila .
pten is also regulated through epigenetic silencing by methylation of the pten promoter [ 80 , 81 ] .
an interesting zinc - finger transcription factor , sal - like protein 4 ( sall4 ) , has been discovered as a critical negative regulator of pten transcription by recruiting an epigenetic repressor complex involving an atpase and a histone deacetylase to the pten promoter .
sall4 plays a critical role in regulating development by modulating self - renewal in stem cells , and its function appears to at least partly involve methylation of the pten promoter and modulation of its transcription .
data on this mechanism are still limited , but to date this process has been shown to regulate kidney patterning during development as well as leukemogenesis .
current research in the area of pten transcriptional regulation continues to be dynamic , and more novel regulation patterns are likely to be discovered in the near future .
recent studies have identified several interesting developmentally expressed mirnas that regulate pten mrna message stability and translatability .
these mirnas typically downregulate pten mrna levels by targeting it for degradation and include mir-17 , mir-19 , and mir-21 [ 8385 ] .
while several examples of mir-17 and mir-19-mediated pten rna levels have been reported in the cancer literature , mir-21 has been described to play a critical role in repair and recovery , a developmental signaling - related process .
for example , in the pancreas , mir-21 regulates injury repair in diabetic models by targeting pten rna for degradation .
inhibition of mir-21 results in autophagy in this model in a manner dependent on pten degradation . in another example of novel mir - related pten regulation ,
the pten pseudogene 1 ( ptenp1 ) acts as a decoy for pten - targeting mirnas and thereby regulates pten expression by coding - independent activity through sequestering these mirnas and effectively inhibiting their effects on pten expression .
additionally , combined bioinformatic and experimental approaches have identified cerna transcripts that control pten expression by sequestering pten - targeting mirnas during development of both prostate and skin .
because this type of pten regulation , and indeed this field of gene regulation in general , is in its infancy , we are only beginning to understand the pten regulation by coding and noncoding cernas .
still , this novel work provides a platform for further studies investigating posttranscriptional regulation patterns of pten expression in both developmental biology and disease conditions .
the protein stability and enzyme activity of pten are regulated in a number of ways at the posttranslational level .
first , pten is phosphorylated in its c - terminal tail at ser380 , thr382 , thr383 , and ser385 , and this functions to inhibit the critical pten phosphatase activity , thereby promoting growth in prostate and kidney cells .
while this may seem like a cellular disconnect , this paradoxical phenomenon is explained by the finding that this closed , more stable pten conformation is prevented from associating with membranes and therefore is geographically separated from its substrates .
pten can also be activated by phosphorylation ; in particular , the c2 domain of pten is phosphorylated at ser229 and thr321 by rhoa - associated protein kinase ( rock ) , a phosphorylation that results in its association with membranes and phosphoinositide substrates , affecting differentiation in leukocytes .
pten is further phosphorylated at tyr336 by the tyr protein kinase rak , and this phosphorylation results in its stabilization .
finally , pten is also phosphorylated at ser370 and thr366 by ck2 and gsk3 [ 91 , 92 ] , respectively ; however , the consequences of this phosphorylation are unclear . the likely extensive signaling networks that regulate these widespread phosphorylations in pten
are not fully studied , but the tgf / bmp - smad developmental pathways are known to regulate pten phosphorylation [ 93 , 94 ] . given the widespread application of smad signaling to developmental biology , the presence of smad - regulated pten phosphorylation is a critical aspect of developmental regulation in cells .
pten is acetylated at lys125lys128 by p300/creb - binding protein- ( cbp- ) associated factor ( pcaf ) and at lys402 by cbp itself .
acetylation at these residues inhibits pten 's function as a phosphatase and has been shown to promote the growth of prostate epithelial cells and glial cells .
in addition , the deacetylase sirtuin 1 ( sirt1 ) is involved in excluding pten from the nucleus and therefore preventing its newly characterized nuclear functions .
the conformation , stability , and subcellular distribution of pten is regulated by critical interactions with other proteins within cells , and these proteins are known to be critical for proper development of a number of organ systems .
the guanylate kinase inverted 2 ( magi2 ) and -arrestins cooperate to enhance pten activity [ 98 , 99 ] .
magi2 phosphorylates pten on threonine residues at positions 382 and 383 of pten 's carboxy terminus , allowing recruitment to cell - cell junctions .
mutations to these residues prevent pten recruitment . upon recruitment , -arrestins modulate pten activity by direct binding to the c2 domain and modulating its protein phosphatase activity , including that at the level of small gtpases including rhoa / rock .
in addition , myosin v regulates pten 's movement to and from the plasma membrane , and this function is required for pten to access its phosphoinositide substrates   and for disrupting the proper regulation of neuronal cell size .
the p85 regulatory subunit of the pi3 kinase enzyme itself interacts with pten in a novel mechanism of repressing the pi3k  akt pathway   independent of pten 's action as a phosphatase .
it is therefore proposed that p85 regulates the pi3k  akt pathway bidirectionally both through its binding to catalytic p110 subunit resulting in the generation of phosphoinositides and by binding pten , leading to repression .
this work proposes a novel signaling model for pten - p85 association , in which p85 preferentially binds and stabilizes p110 preferentially when p85 levels are low , but excess p85 binds to and positively regulates pten phosphatase activity when p110 is saturated .
therefore , sustained activation of pi3k signaling and activated p110-p85 complexing is modulated homeostatically by this mechanism .
a fascinating group of recent studies have utilized proteomic library screens to identify further novel pten interacting proteins .
first , the na / h exchanger regulatory factor ( nherf ) binds to and recruits pten to the platelet - derived growth factor receptor ( pdgfr ) .
this represents another action that restricts pi3k  akt pathway activation , independent of phosphatase activity .
this has the effect of inhibiting pdgf - induced cytoskeletal rearrangements and chemotactic migration of developing neurons .
in addition , the mammalian disks large homologue 1 ( dlg1 ) , magi-2 , and mast205 proteins directly interact with pten and enhance pten stability and activity .
further , neuregulin 1 ( nrg1 ) has been shown to interact with both dlg1 and pten in a stable complex that has the effect of regulating myelin sheath thickness in developing mouse sciatic nerves .
additional but less - characterized protein - protein interactions that modulate pten function include the pip3-dependent rac exchanger factor 2a ( prex2a ) , shank - interacting protein - like 1 ( sipl1 ) , and -mannosidase 2c1 ( man2c1 ) .
pten is critically important in regulating signaling pathways involved in cell growth and animal development . through its
well - characterized function as a phosphatase of pip3 , pten modulates a network of mitogen - activated signals transduced through pi3k  akt signaling .
this primary action of pten has tremendous impact on cell growth , cell migration , cell death , and cell differentiation 
the active phosphorylated pip3 activates several signaling molecules including the phosphatidylinositol - dependent kinases ( pdks ) , followed by akt , s6 kinase , and mtor . beyond this ,
akt 's targets include the apoptotic factor bad , activator and executioner caspases , glycogen synthase kinase-3 ( gsk-3 ) , mdm2 , p21 and p27 , forkhead transcription factors ( foxos ) , and nuclear receptors including the androgen and estrogen receptors .
akt - mediated phosphorylation of these molecules causes activation , translocation , and increased stability .
the pten / pi3 kinase / akt signaling cascade crosstalks to several key signal transduction pathways that are critical to developmental biology .
the tgf-/smad pathway is one of the most seminal pathways in developmental biology , and pten modulates tgf/smad signaling by reversing akt - mediated phosphorylation of smad3 , the critical signaling intermediate of tgf/smad signaling .
similarly , the wnt signaling pathway is indispensable for properly regulated development , cellular proliferation , and differentiation .
pten regulates this pathway by reversing akt kinase phosphorylation and inhibition of gsk-3 , resulting in -catenin nuclear translocation and activation .
finally , recent studies demonstrate that pten regulates the expression and action of the homeobox genes nkx3.1 and hepatic nuclear factor , proteins that are critical to organ development . the scientific literature in the field of tissue stem or stem - like  progenitor  cells and their role in tissue development , growth , recovery and repair has become beyond extensive in recent years .
expansion of stem / progenitor cells is a hallmark of growth and patterning during development , and regulation of these cells , including their proliferation , maintenance , and differentiation , is a critical factor of developmental regulation . because of this , a review of the current literature on pten 's role in stem and tissue progenitor cells is warranted in this review .
pten plays an important role in regulating the homeostasis of stem / progenitor cells in multiple tissues .
interestingly , pten regulates both self - renewal and proliferation , but paradoxically it also plays a role in stem cell exhaustion .
for example , the foxo family of transcription factors controls stem cell proliferation and survival in hematopoietic stem cells , and pten signaling is a critical modulator of foxo activity .
foxo3a - deficient hscs exhibit increased proliferation rate , decreased quiescence , and a reduced ability to repopulate bone marrow after transplantation into recipient mice . additionally , the previously mentioned wnt/-catenin signaling pathway is critical for hsc self - renewal , and its activation is well known to be modulated by pten .
interestingly , pten loss and akt activation in hscs lead to a moderate increase in the level of unphosphorylated -catenin , but this is not sufficient to maintain pten - null hsc self - renewal .
finally , notch signaling plays a key role in regulating neural stem cell expansion   and , as stated previously , notch pathway activation leads to reduced pten expression in neural and hematopoietic stem cells .
pten acts as the key endogenous negative modulator of phosphoinositide signaling in mammalian cells , and therefore its role in normal cell homeostasis , proliferation , apoptosis , and many additional components of cell biology is extensive . because pten regulates cancer progression , much of what has been studied regarding pten relates to tumorigenesis and tumor growth .
while this is warranted because of the relevance of cancer to human health , pten has substantial but underappreciated effects in normal tissue and organ development , immune system development and regulation , axonal regeneration , glucose regulation , and benign growth disorders .
pten is often dogmatically thought of as a constitutive protein that exhibits lost activity during diseases , but what is underappreciated is that pten has a very complex regulation network that involves signaling pathways that regulate pten transcription , transcript stability , posttranslational modifications , protein - protein interactions , and cellular location .
pten then in turn regulates numerous developmental signaling networks that are critical to development and adult tissue maintenance .
 phosphatase and tensin homologue ( pten ) is a critical cell endogenous inhibitor of phosphoinositide signaling in mammalian cells . 
 pten dephosphorylates phosphoinositide trisphosphate ( pip3 ) , and by so doing pten has the function of negative regulation of akt , thereby inhibiting this key intracellular signal transduction pathway . 
 in numerous cell types , pten loss - of - function mutations result in unopposed akt signaling , producing numerous effects on cells . 
 numerous reports exist regarding mutations in pten leading to unregulated akt and human disease , most notably cancer . 
 however , less is commonly known about nonmutational regulation of pten . 
 this review focuses on an emerging literature on the regulation of pten at the transcriptional , posttranscriptional , translational , and posttranslational levels . 
 specifically , a focus is placed on the role developmental signaling pathways play in pten regulation ; this includes insulin - like growth factor , notch , transforming growth factor , bone morphogenetic protein , wnt , and hedgehog signaling . the regulation of pten by developmental mediators affects critical biological processes including neuronal and organ development , stem cell maintenance , cell cycle regulation , inflammation , response to hypoxia , repair and recovery , and cell death and survival . 
 perturbations of pten regulation consequently lead to human diseases such as cancer , chronic inflammatory syndromes , developmental abnormalities , diabetes , and neurodegeneration . 
1. Introduction
2. PTEN in Developmental Biology
3. PTEN Regulation as Part of Developmental Signaling
4. Conclusions