smad8 protein


Summary: A receptor-regulated smad protein that undergoes PHOSPHORYLATION by BONE MORPHOGENETIC PROTEIN RECEPTORS and regulates BONE MORPHOGENETIC PROTEIN signaling.

Top Publications

  1. Orvis G, Jamin S, Kwan K, Mishina Y, Kaartinen V, Huang S, et al. Functional redundancy of TGF-beta family type I receptors and receptor-Smads in mediating anti-Mullerian hormone-induced Mullerian duct regression in the mouse. Biol Reprod. 2008;78:994-1001 pubmed publisher
    ..Loss of these genes in the Müllerian duct mesenchyme results in male infertility due to retention of Müllerian duct derivatives in an otherwise virilized male. ..
  2. Faure S, Lee M, Keller T, ten Dijke P, Whitman M. Endogenous patterns of TGFbeta superfamily signaling during early Xenopus development. Development. 2000;127:2917-31 pubmed
    ..We discuss the implications of our results for endogenous functions of BMP and activin-like signals as candidate morphogens regulating primary germ layer formation and dorsoventral patterning of the early Xenopus embryo. ..
  3. Pangas S, Li X, Umans L, Zwijsen A, Huylebroeck D, Gutierrez C, et al. Conditional deletion of Smad1 and Smad5 in somatic cells of male and female gonads leads to metastatic tumor development in mice. Mol Cell Biol. 2008;28:248-57 pubmed
    ..These data strongly implicate the BR-SMADs as part of a critical developmental pathway in ovaries and testis that, when disrupted, leads to malignant transformation...
  4. David L, Mallet C, Mazerbourg S, Feige J, Bailly S. Identification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cells. Blood. 2007;109:1953-61 pubmed
    ..Taken together, our results suggest that BMP9 and BMP10 are two specific ALK1 ligands that may physiologically trigger the effects of ALK1 on angiogenesis. ..
  5. Oxburgh L, Robertson E. Dynamic regulation of Smad expression during mesenchyme to epithelium transition in the metanephric kidney. Mech Dev. 2002;112:207-11 pubmed
    ..Down-regulation is complete in lithium chloride induced mesenchymal condensates, indicating that Smad regulation takes place at an early stage, prior to mesenchyme to epithelium transition. ..
  6. Vrljicak P, Myburgh D, Ryan A, Van Rooijen M, Mummery C, Gupta I. Smad expression during kidney development. Am J Physiol Renal Physiol. 2004;286:F625-33 pubmed
    ..Based on the observed patterns of expression, we speculate that individual or combinations of Smads may play specific roles in cell-fate determination during kidney development. ..
  7. Lee H, Farhanullah -, Lee J, Jajoo R, Kong S, Shin J, et al. Discovery of a Small Molecule that Enhances Astrocytogenesis by Activation of STAT3, SMAD1/5/8, and ERK1/2 via Induction of Cytokines in Neural Stem Cells. ACS Chem Neurosci. 2016;7:90-9 pubmed publisher
    ..Taken together, our results suggest that these small molecules can serve as a useful tool to study cell fate determination in NSCs and be used as an inexpensive alternative to cytokines to study mechanisms of astrocytogenesis. ..
  8. Hester M, Thompson J, Mills J, Liu Y, El Hodiri H, Weinstein M. Smad1 and Smad8 function similarly in mammalian central nervous system development. Mol Cell Biol. 2005;25:4683-92 pubmed
    ..5. These observations suggest that BMP-responsive Smads have critical functions in the development of the mammalian central nervous system. ..
  9. Scholl C, Weiβmüller K, Holenya P, Shaked Rabi M, Tucker K, Wolfl S. Distinct and overlapping gene regulatory networks in BMP- and HDAC-controlled cell fate determination in the embryonic forebrain. BMC Genomics. 2012;13:298 pubmed
    ..STAT3 and SMAD1/5/8 interact synergistically to promote astrogliogenesis, and thus we show for the first time that HDACs act to suppress BMP-promoted astrogliogenesis by suppression of the crucial partner STAT3. ..

More Information


  1. Kua H, Liu H, Leong W, Li L, Jia D, Ma G, et al. c-Abl promotes osteoblast expansion by differentially regulating canonical and non-canonical BMP pathways and p16INK4a expression. Nat Cell Biol. 2012;14:727-37 pubmed publisher
    ..These findings identify c-Abl as a regulator of BMP signalling pathways and uncover a role for c-Abl in p16(INK4a) expression and osteoprogenitor expansion. ..
  2. Liu J, Saito K, Maruya Y, Nakamura T, Yamada A, Fukumoto E, et al. Mutant GDF5 enhances ameloblast differentiation via accelerated BMP2-induced Smad1/5/8 phosphorylation. Sci Rep. 2016;6:23670 pubmed publisher
    ..These results suggest that mutant GDF5 enhances ameloblast differentiation via accelerated BMP2-signalling. ..
  3. Lorda Diez C, Torre Pérez N, Garcia Porrero J, Hurle J, Montero J. Expression of Id2 in the developing limb is associated with zones of active BMP signaling and marks the regions of growth and differentiation of the developing digits. Int J Dev Biol. 2009;53:1495-502 pubmed publisher
    ..These data suggest that Id2 is a molecular mediator of BMP signaling acting in concert with the TGFbeta pathway during the formation of the digits. ..
  4. Okuyama N, Kiryu Seo S, Kiyama H. Altered expression of Smad family members in injured motor neurons of rat. Brain Res. 2007;1132:36-41 pubmed
    ..Immunohistochemistry and Western blotting analysis confirmed the alterations of Smad1, 2 and 4 in injured neurons. These results suggest that the Smad signaling may be important for nerve regeneration. ..
  5. Lee S, Kim S, Park S, Kim J, Jang J, Kim E. Effects of recombinant dentin sialoprotein in dental pulp cells. J Dent Res. 2012;91:407-12 pubmed publisher
  6. Nishida T, Kubota S, Aoyama E, Takigawa M. Impaired glycolytic metabolism causes chondrocyte hypertrophy-like changes via promotion of phospho-Smad1/5/8 translocation into nucleus. Osteoarthritis Cartilage. 2013;21:700-9 pubmed publisher
    ..These findings suggest that decreased ATP production by NaF promotes hypertrophy-like changes via activation of phospho-Smad1/5/8 in the presence of lactate. Novel metabolic aspects of OA pathogenesis are indicated herein. ..
  7. Park E, Woods D, Tilly J. Bone morphogenetic protein 4 promotes mammalian oogonial stem cell differentiation via Smad1/5/8 signaling. Fertil Steril. 2013;100:1468-75 pubmed publisher
  8. Girerd B, Montani D, Jaïs X, Eyries M, Yaici A, Sztrymf B, et al. Genetic counselling in a national referral centre for pulmonary hypertension. Eur Respir J. 2016;47:541-52 pubmed publisher
    ..BMPR2 screening allowed us to offer pre-implantation diagnosis to two couples with a BMPR2 mutation.Genetic counselling can be implemented in pulmonary hypertension centres. ..
  9. Ishida K, Haudenschild D. Interactions between FGF21 and BMP-2 in osteogenesis. Biochem Biophys Res Commun. 2013;432:677-82 pubmed publisher
    ..In summary, this study demonstrates interactions between BMP-2 and FGF21 pathways exist in vitro, and that FGF21 enhances the osteogenic activity of BMP-2 by up-regulating the BMP-2-dependent Smad signaling pathway. ..
  10. Lorente Trigos A, Varnat F, Melotti A, Ruiz i Altaba A. BMP signaling promotes the growth of primary human colon carcinomas in vivo. J Mol Cell Biol. 2010;2:318-32 pubmed publisher
    ..In contrast, we raise the possibility that blockade of BMP signaling might have beneficial effects against at least a subset of advanced colon cancers. ..
  11. Liu S, Tian Z, Yin F, Zhang P, W Y, Ding X, et al. Expression and functional roles of Smad1 and BMPR-IB in glioma development. Cancer Invest. 2009;27:734-40 pubmed publisher
    ..The effects could be blocked by cotransfection of Smad6. These results might provide new molecular marker and target for glioma diagnosis and therapy. ..
  12. Costamagna D, Quattrocelli M, van Tienen F, Umans L, de Coo I, Zwijsen A, et al. Smad1/5/8 are myogenic regulators of murine and human mesoangioblasts. J Mol Cell Biol. 2016;8:73-87 pubmed publisher
    ..Moreover, using a transgenic mouse model of Smad8 deletion, we demonstrated that the absence of SMAD8 protein improved MAB myogenic differentiation...
  13. Anhê F, Lellis Santos C, Leite A, Hirabara S, Boschero A, Curi R, et al. Smad5 regulates Akt2 expression and insulin-induced glucose uptake in L6 myotubes. Mol Cell Endocrinol. 2010;319:30-8 pubmed publisher
    ..The present study indicates that Smad5 regulates glucose uptake in skeletal muscle by controlling Akt2 expression and phosphorylation. These finding reveals Smad5 as a potential target for the therapeutic of type 2 diabetes. ..
  14. Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet. 2009;46:331-7 pubmed publisher
    ..We describe the first mutation in SMAD8 in a patient with IPAH. Our findings suggest the involvement of SMAD8 in the pathogenesis of PAH. ..
  15. Kersten C, Sivertsen E, Hystad M, Forfang L, Smeland E, Myklebust J. BMP-6 inhibits growth of mature human B cells; induction of Smad phosphorylation and upregulation of Id1. BMC Immunol. 2005;6:9 pubmed
    ..Furthermore, B cells were demonstrated to upregulate BMP-6 mRNA upon stimulation with anti-IgM. In mature human B cells, BMP-6 inhibited cell growth, and rapidly induced phosphorylation of Smad1/5/8 followed by an upregulation of Id1. ..
  16. Suzuki T, Hasso S, Fallon J. Unique SMAD1/5/8 activity at the phalanx-forming region determines digit identity. Proc Natl Acad Sci U S A. 2008;105:4185-90 pubmed publisher
    ..Our data define the molecular profile of the PFR, and we propose a model for understanding formation and variation of digits during autopodial development. ..
  17. Hsu Y, Chang J, Tsai C, Chien T, Kuo P. Myricetin induces human osteoblast differentiation through bone morphogenetic protein-2/p38 mitogen-activated protein kinase pathway. Biochem Pharmacol. 2007;73:504-14 pubmed
  18. Attisano L, Silvestri C, Izzi L, Labbe E. The transcriptional role of Smads and FAST (FoxH1) in TGFbeta and activin signalling. Mol Cell Endocrinol. 2001;180:3-11 pubmed
    ..Thus, it is the interaction of Smads with a wide range of specific transcriptional partners that is important for the generation of diverse biological responses to TGFbeta superfamily members. ..
  19. Retting K, Song B, Yoon B, Lyons K. BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation. Development. 2009;136:1093-104 pubmed publisher
    ..Finally, we tested whether FGF exerts its antagonistic effects directly through Smad linker phosphorylation. The results support the alternative conclusion that the effects of FGFs on BMP signaling are indirect in vivo. ..
  20. Cao Y, Yang W, Tyler M, Gao X, Duan C, Kim S, et al. Noggin attenuates cerulein-induced acute pancreatitis and impaired autophagy. Pancreas. 2013;42:301-7 pubmed publisher
    ..Bone morphogenetic protein signaling seems to promote AP induction and autophagy, as suggested by our study showing that noggin ameliorates AP and partially restores autophagic homeostasis. ..
  21. Babitt J, Zhang Y, Samad T, Xia Y, Tang J, Campagna J, et al. Repulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptor. J Biol Chem. 2005;280:29820-7 pubmed
    ..Finally, we demonstrate that BMP signaling occurs in neurons that express RGMa in vivo. These data are consistent with a role for RGMa as a BMP co-receptor. ..
  22. Perotti C, Karayazi O, Moffat S, Shemanko C. The bone morphogenetic protein receptor-1A pathway is required for lactogenic differentiation of mammary epithelial cells in vitro. In Vitro Cell Dev Biol Anim. 2012;48:377-84 pubmed publisher
    ..This evidence functionally identifies BMPR1A as a potential new regulator of mammary epithelial alveolar cell differentiation. ..
  23. Corbett H, Connell M, Fernig D, Losty P, Jesudason E. ANG-1 TIE-2 and BMPR signalling defects are not seen in the nitrofen model of pulmonary hypertension and congenital diaphragmatic hernia. PLoS ONE. 2012;7:e35364 pubmed publisher
    ..In PH and CDH defects of ANG-1/TIE-2/BMPR-related signalling are not essential for the lethal vasculopathy. ..
  24. Takatoh J, Wang F. Axonally translated SMADs link up BDNF and retrograde BMP signaling. Neuron. 2012;74:3-5 pubmed publisher
  25. Shola D, Wang H, Wahdan Alaswad R, Danielpour D. Hic-5 controls BMP4 responses in prostate cancer cells through interacting with Smads 1, 5 and 8. Oncogene. 2012;31:2480-90 pubmed publisher
    ..Collectively, these results provide the first evidence for a physical and mutual functional interaction between Hic-5 and the BMP signaling pathway. ..
  26. Macias Silva M, Hoodless P, Tang S, Buchwald M, Wrana J. Specific activation of Smad1 signaling pathways by the BMP7 type I receptor, ALK2. J Biol Chem. 1998;273:25628-36 pubmed
    ..Furthermore, we show that ALK1 (TSRI), an orphan receptor that is closely related to ALK2 also mediates Smad1 signaling. Thus, ALK1 and ALK2 induce Smad1-dependent pathways and ALK2 functions to mediate BMP7 but not activin signaling. ..
  27. Hoffmann A, Pelled G, Turgeman G, Eberle P, Zilberman Y, Shinar H, et al. Neotendon formation induced by manipulation of the Smad8 signalling pathway in mesenchymal stem cells. J Clin Invest. 2006;116:940-52 pubmed
    ..These findings may have considerable importance for the therapeutic replacement of tendons or ligaments and for engineering other tissues in which BMP plays a pivotal developmental role. ..
  28. Zoukhri D, Fix A, Alroy J, Kublin C. Mechanisms of murine lacrimal gland repair after experimentally induced inflammation. Invest Ophthalmol Vis Sci. 2008;49:4399-406 pubmed publisher
    ..The lacrimal gland contains stem/progenitor cells capable of tissue repair after injury. Programmed cell death after injury triggers proliferation and differentiation of these cells, presumably through activation of the BMP7 pathway. ..
  29. Hami D, Grimes A, Tsai H, Kirby M. Zebrafish cardiac development requires a conserved secondary heart field. Development. 2011;138:2389-98 pubmed publisher
  30. Jang W, Kim E, Lee K, Son H, Koh J. AMP-activated protein kinase (AMPK) positively regulates osteoblast differentiation via induction of Dlx5-dependent Runx2 expression in MC3T3E1 cells. Biochem Biophys Res Commun. 2011;404:1004-9 pubmed publisher
    ..These results suggest that the activation of AMPK stimulates osteoblast differentiation via the regulation of Smad1/5/8-Dlx5-Runx2 signaling pathway. ..
  31. Hellingman C, Davidson E, Koevoet W, Vitters E, van den Berg W, van Osch G, et al. Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of Smad1/5/8P prevents terminal differentiation and calcification. Tissue Eng Part A. 2011;17:1157-67 pubmed publisher
    ..This indicates that while Smad2/3P is important for continuation of collagen II deposition, Smad1/5/8 phosphorylation is associated with terminal differentiation and mineralization. ..
  32. Yu X, Li J, Liu H, Li X, Chen S, Zhang H, et al. Identification and expression of amphioxus AmphiSmad1/5/8 and AmphiSmad4. Sci China Life Sci. 2011;54:220-6 pubmed publisher
    ..Moreover, AmphiSmad1/5/8 and AmphiSmad4 showed extensive distribution in all adult tissues examined, suggesting that these two genes may play important roles in the morphogenesis of a variety of tissues especially notochord and gonad. ..
  33. Blank U, Seto M, Adams D, Wojchowski D, Karolak M, Oxburgh L. An in vivo reporter of BMP signaling in organogenesis reveals targets in the developing kidney. BMC Dev Biol. 2008;8:86 pubmed publisher
  34. Liang Y, Zhao S, Chang X, Du H. [Effect of bushen tiaojing recipe on the expressions of Smad1, Smad5, Smad8, and Smad4 in human mural granulosa cells]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013;33:606-10 pubmed
    ..The mechanisms of BTR for improving the pregnancy rate and the ovarian functions might be correlated with up-regulating mRNA and protein expressions of Smadl of human mural granulosa cells. ..
  35. Morty R, Nejman B, Kwapiszewska G, Hecker M, Zakrzewicz A, Kouri F, et al. Dysregulated bone morphogenetic protein signaling in monocrotaline-induced pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol. 2007;27:1072-8 pubmed
    ..BMP signaling and BMP-regulated physiological phenomena are perturbed in MCT-treated rats, lending solid support to the proposed roles for BMP signaling in the pathogenesis of human PAH. ..
  36. Markic D, Celić T, Spanjol J, Grsković A, Bobinac D, Fuckar Z. Expression of bone morphogenetic protein-7, its receptors and Smad1/5/8 in normal human kidney and renal cell cancer. Coll Antropol. 2010;34 Suppl 2:149-53 pubmed
    ..BMP-7, BMP receptors and pSmad1/5/8 were showed in normal kidney and RCC. Detected alterations of BMP-7, BMP receptors and pSmad expression in RCC suggested their possible role in tumorigenesis of kidney cancer. ..
  37. Chen L, Dong S, Liu J, Tao X, Tang K, Xu J. Synergy of tendon stem cells and platelet-rich plasma in tendon healing. J Orthop Res. 2012;30:991-7 pubmed publisher
  38. Abarca Buis R, Bustamante M, Cuervo R, Aguilar Fern ndez de Lara D, Chimal Monroy J. Smad8 is expressed in the anterior necrotic zone: evidence for a role of bone morphogenetic proteins/SMAD signaling in the activation of a molecular cascade that culminates in cell death. Dev Growth Differ. 2011;53:780-92 pubmed publisher
    ..These results suggest that BMPs mediated by SMAD signaling activate a molecular cascade that culminates in PCD...
  39. Arnold S, Maretto S, Islam A, Bikoff E, Robertson E. Dose-dependent Smad1, Smad5 and Smad8 signaling in the early mouse embryo. Dev Biol. 2006;296:104-18 pubmed
    ..These experiments demonstrate for the first time that Smad1 and Smad5 function cooperatively to govern BMP target gene expression in the early mammalian embryo. ..
  40. Russo A, Thiagalingam A, Pan H, Califano J, Cheng K, Ponte J, et al. Differential DNA hypermethylation of critical genes mediates the stage-specific tobacco smoke-induced neoplastic progression of lung cancer. Clin Cancer Res. 2005;11:2466-70 pubmed
    ..We also provide preliminary evidence that peripheral lymphocytes could potentially be used as a surrogate for bronchial epithelial cells to detect altered DNA methylation in smokers. ..
  41. Nishita M, Ueno N, Shibuya H. Smad8B, a Smad8 splice variant lacking the SSXS site that inhibits Smad8-mediated signalling. Genes Cells. 1999;4:583-91 pubmed
    ..Smad8B inhibited BMP signalling. Smad8 and Smad8B thus represent novel signal transduction proteins that may regulate the BMP signalling pathway. ..
  42. Pardali K, Kowanetz M, Heldin C, Moustakas A. Smad pathway-specific transcriptional regulation of the cell cycle inhibitor p21(WAF1/Cip1). J Cell Physiol. 2005;204:260-72 pubmed
    ..Thus, p21 is a common target of all TGF-beta superfamily pathways. However, the ability of TGF-beta superfamily members to induce cell growth arrest depends on the regulation of additional gene targets. ..
  43. Drake K, Dunmore B, McNelly L, Morrell N, Aldred M. Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension. Am J Respir Cell Mol Biol. 2013;49:403-9 pubmed publisher
    ..Approximately 29% of all HPAH mutations are nonsense point mutations. In light of this, we propose ataluren as a potential new personalized therapy for this significant subgroup of patients with PAH. ..
  44. Mottershead D, Ritter L, Gilchrist R. Signalling pathways mediating specific synergistic interactions between GDF9 and BMP15. Mol Hum Reprod. 2012;18:121-8 pubmed publisher
    ..This synergistic interaction is targeted at the SMAD3 pathway, and is dependent on ERK1/2 and SRC kinase signalling. ..
  45. Nakayama T, Snyder M, Grewal S, Tsuneizumi K, Tabata T, Christian J. Xenopus Smad8 acts downstream of BMP-4 to modulate its activity during vertebrate embryonic patterning. Development. 1998;125:857-67 pubmed
  46. Ryan J, Ryan E, Fabre A, Lawless M, Crowe J. Defective bone morphogenic protein signaling underlies hepcidin deficiency in HFE hereditary hemochromatosis. Hepatology. 2010;52:1266-73 pubmed publisher
    ..of the BMP target genes hepcidin and Id1 was observed, and diminished phosphorylation of Smad1/Smad5/Smad8 protein relative to iron burden was found upon immunohistochemical analysis, suggesting that impaired BMP signaling ..
  47. Miyai K, Yoneda M, Hasegawa U, Toita S, Izu Y, Hemmi H, et al. ANA deficiency enhances bone morphogenetic protein-induced ectopic bone formation via transcriptional events. J Biol Chem. 2009;284:10593-600 pubmed publisher
    ..Immunoprecipitation assay indicated that ANA interacts with Smad8. Thus, ANA is a suppressor of ectopic bone formation induced by BMP, and this inhibitory ANA activity is a part of the negative feedback regulation of BMP function. ..
  48. Ishibashi O, Ikegame M, Takizawa F, Yoshizawa T, Moksed M, Iizawa F, et al. Endoglin is involved in BMP-2-induced osteogenic differentiation of periodontal ligament cells through a pathway independent of Smad-1/5/8 phosphorylation. J Cell Physiol. 2010;222:465-73 pubmed publisher
    ..These results, taken together, raise a possibility that PDL cells respond to BMP-2 via a unique signaling pathway dependent on endoglin, which is involved in the osteoblastic differentiation and mineralization of the cells. ..
  49. Hegarty S, O Keeffe G, Sullivan A. BMP-Smad 1/5/8 signalling in the development of the nervous system. Prog Neurobiol. 2013;109:28-41 pubmed publisher
    ..Finally, this review discusses the neurodevelopmental abnormalities associated with the knockdown of Smad 1/5/8. ..
  50. Tanikawa R, Tanikawa T, Hirashima M, Yamauchi A, Tanaka Y. Galectin-9 induces osteoblast differentiation through the CD44/Smad signaling pathway. Biochem Biophys Res Commun. 2010;394:317-22 pubmed publisher
    ..Because Smad1 is phosphorylated by BMP receptors, we propose that formation of the CD44/BMP receptor complex induced by galectin-9 may provide a trigger for the activation of Smads. ..
  51. Kautz L, Meynard D, Monnier A, Darnaud V, Bouvet R, Wang R, et al. Iron regulates phosphorylation of Smad1/5/8 and gene expression of Bmp6, Smad7, Id1, and Atoh8 in the mouse liver. Blood. 2008;112:1503-9 pubmed publisher
    ..This study points out molecules that appear to play a critical role in the control of systemic iron balance. ..
  52. Kawai S, Faucheu C, Gallea S, Spinella Jaegle S, Atfi A, Baron R, et al. Mouse smad8 phosphorylation downstream of BMP receptors ALK-2, ALK-3, and ALK-6 induces its association with Smad4 and transcriptional activity. Biochem Biophys Res Commun. 2000;271:682-7 pubmed
    ..The presence of Smad8 mRNA in mouse calvaria cells and osteoblasts suggests a role of Smad8 in the osteoblast differentiation and maturation. ..
  53. Wahdan Alaswad R, Bane K, Song K, Shola D, Garcia J, Danielpour D. Inhibition of mTORC1 kinase activates Smads 1 and 5 but not Smad8 in human prostate cancer cells, mediating cytostatic response to rapamycin. Mol Cancer Res. 2012;10:821-33 pubmed publisher
    ..Taken together, our data implicate Smads 1, 5 and 8 as potential prognostic markers and therapeutic targets for mTOR inhibition therapy of prostate cancer. ..