Signal transducer and activator of transcription 5A is a protein that in humans is encoded by the STAT5Agene.[1][2]STAT5Aorthologs[3] have been identified in several placentals for which complete genome data are available.
STAT5a shares the same six functional domains as the other members of the STAT family. It contains 20 amino acids unique to its C-terminal domain and is 96% similar to its homolog, STAT5b. The six functional domains and their corresponding amino acid positions are as follows:
N-Terminal domain (aa1-144): stabilized interactions to form tetramers
Coiled-coil domain (aa145-330): interacts with chaperones and facilitates protein-protein interactions for transcriptional regulation
DNA binding domain (aa331-496): permits binding to consensus gamma-interferon activation sequence (GAS)
Linker domain (aa497-592): stabilizes DNA binding
Src Homology 2 domain (aa593-685): mediates receptor-specific recruitment and STAT dimerization via phosphorylated tyrosine residue
Transcriptional activation domain (aa702-794): interacts with critical co-activators
In addition to the six functional domains, specific amino acids have been identified as key mediators of STAT5a function. Phosphorylation of tyrosine 694 and glycosylation of threonine 92 are important for STAT5a activity. Mutation of serine 710 to phenylalanine results in constitutive activation.[4][5]
Function
The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein is activated by, and mediates the responses of many cell ligands, such as IL2, IL3, IL7 GM-CSF, erythropoietin, thrombopoietin, and different growth hormones. Activation of this protein in myeloma and lymphoma associated with a TEL/JAK2 gene fusion is independent of cell stimulus and has been shown to be essential for the tumorigenesis. The mouse counterpart of this gene is found to induce the expression of BCL2L1/BCL-X(L), which suggests the antiapoptotic function of this gene in cells.[6] It also transduces prolactin signals to the milk protein genes and is necessary for mammary gland development.[7]
STAT5a and cancer
Many studies have indicated a key role of STAT5a in leukemia, breast, colon, head and neck, and prostate cancer.[4][7][8][9] Until recently, the unique characteristics and function of STAT5a in these cancers have not been delineated from STAT5b, and more research into their differential behavior is warranted. Because of its integral role in immune cell development, STAT5a may contribute to tumor development by compromising immune surveillance.[7]
STAT5a expression has been studied closely in prostate and breast cancer, and has only recently shown some promise with colorectal and head and neck cancer. Unphosphorylated or inactive STAT5a may suppress tumor growth in colorectal cancer and active STAT5a expression in premalignant and tumor lesions has shown potential as a prognostic marker in oral squamous cell carcinoma.[7][10]
Prostate Cancer
STAT5a is involved in the maintenance of integrated prostate epithelial structure and has been shown to be critical for cell viability and tumor growth. Stat5a/b is persistently active in prostate cancer cells and inhibition of STAT5a/b has resulted in large scale apoptotic death, although the specific role of STAT5a and distribution of activity remains largely unknown.[4] Prolactin has been known to activate the JAK2-STAT5a/b pathway in both normal and malignant prostate epithelium, but again, the specific activity of STAT5a remains unknown.[5]
Breast Cancer
In normal tissue, STAT5a mediates effects of prolactin in mammary glands. In breast cancer, STAT5a signaling is important for maintain tumor differentiation and suppressing disease progression. Studies originally showed a correlation between high STAT5a expression and tumor differentiation in mice models, but histopathological analysis of human breast cancer tissue has shown a different trend. It was shown that low nuclear levels of STAT5a was associated with unfavorable clinical outcomes and cancer progression independent of STAT5b expression. High STAT5a was suggested to be an inhibitor of invasion and metastasis and therefore an indicator of favorable clinical outcomes. Because of these trends, it has been proposed as a predictor of response to therapies such as anti-estrogen treatment.[8][11]
Therapeutic Treatment Approaches
Because the specific activity of STAT5a has not been extensively investigated, most potential therapeutic treatments aim to target STAT5a/b. So far, the only reported potential therapeutic benefit specific to STAT5a has been in colorectal cancer. Inhibition of STAT5a alone would not effect colorectal cancer cells, but when combined with chemotherapies such as cisplatin, it could increase the chemosensitivity of the cancer cells to the drugs.[9] Therapy schemes currently focus on STAT5a/b, targeting and inhibiting different mediators of the JAK2-STAT5 pathway.[4]
↑Hou J, Schindler U, Henzel WJ, Wong SC, McKnight SL (May 1995). "Identification and purification of human Stat proteins activated in response to interleukin-2". Immunity. 2 (4): 321–9. doi:10.1016/1074-7613(95)90140-X. PMID7719937.
↑Lin JX, Mietz J, Modi WS, John S, Leonard WJ (July 1996). "Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells". J. Biol. Chem. 271 (18): 10738–44. doi:10.1074/jbc.271.18.10738. PMID8631883.
↑ 9.09.1Zhang, Yanqiao (2012). "STAT5a-targeting miRNA enhances chemosensitivity to cisplatin and 5-fluorouracil in human colorectal cancer cells". Molecular Medicine Reports. doi:10.3892/mmr.2012.801.
↑Ota J, Kimura F, Sato K, Wakimoto N, Nakamura Y, Nagata N, Suzu S, Yamada M, Shimamura S, Motoyoshi K (November 1998). "Association of CrkL with STAT5 in hematopoietic cells stimulated by granulocyte-macrophage colony-stimulating factor or erythropoietin". Biochem. Biophys. Res. Commun. 252 (3): 779–86. doi:10.1006/bbrc.1998.9445. PMID9837784.
↑Olayioye MA, Beuvink I, Horsch K, Daly JM, Hynes NE (June 1999). "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases". J. Biol. Chem. 274 (24): 17209–18. doi:10.1074/jbc.274.24.17209. PMID10358079.
↑Chin H, Nakamura N, Kamiyama R, Miyasaka N, Ihle JN, Miura O (December 1996). "Physical and functional interactions between Stat5 and the tyrosine-phosphorylated receptors for erythropoietin and interleukin-3". Blood. 88 (12): 4415–25. PMID8977232.
↑ 17.017.1Fujitani Y, Hibi M, Fukada T, Takahashi-Tezuka M, Yoshida H, Yamaguchi T, Sugiyama K, Yamanaka Y, Nakajima K, Hirano T (February 1997). "An alternative pathway for STAT activation that is mediated by the direct interaction between JAK and STAT". Oncogene. 14 (7): 751–61. doi:10.1038/sj.onc.1200907. PMID9047382.
↑Barahmand-Pour F, Meinke A, Groner B, Decker T (May 1998). "Jak2-Stat5 interactions analyzed in yeast". J. Biol. Chem. 273 (20): 12567–75. doi:10.1074/jbc.273.20.12567. PMID9575217.
↑Pircher TJ, Petersen H, Gustafsson JA, Haldosén LA (April 1999). "Extracellular signal-regulated kinase (ERK) interacts with signal transducer and activator of transcription (STAT) 5a". Mol. Endocrinol. 13 (4): 555–65. doi:10.1210/mend.13.4.0263. PMID10194762.
↑Dinerstein-Cali H, Ferrag F, Kayser C, Kelly PA, Postel-Vinay M (August 2000). "Growth hormone (GH) induces the formation of protein complexes involving Stat5, Erk2, Shc and serine phosphorylated proteins". Mol. Cell. Endocrinol. 166 (2): 89–99. doi:10.1016/S0303-7207(00)00277-X. PMID10996427.
↑Zhu M, John S, Berg M, Leonard WJ (January 1999). "Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling". Cell. 96 (1): 121–30. doi:10.1016/S0092-8674(00)80965-4. PMID9989503.
↑Yu CL, Jin YJ, Burakoff SJ (January 2000). "Cytosolic tyrosine dephosphorylation of STAT5. Potential role of SHP-2 in STAT5 regulation". J. Biol. Chem. 275 (1): 599–604. doi:10.1074/jbc.275.1.599. PMID10617656.
↑Chughtai N, Schimchowitsch S, Lebrun JJ, Ali S (August 2002). "Prolactin induces SHP-2 association with Stat5, nuclear translocation, and binding to the beta-casein gene promoter in mammary cells". J. Biol. Chem. 277 (34): 31107–14. doi:10.1074/jbc.M200156200. PMID12060651.
Further reading
Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW (2002). "Signaling through the JAK/STAT pathway, recent advances and future challenges". Gene. 285 (1–2): 1–24. doi:10.1016/S0378-1119(02)00398-0. PMID12039028.
Buitenhuis M, Coffer PJ, Koenderman L (2004). "Signal transducer and activator of transcription 5 (STAT5)". Int. J. Biochem. Cell Biol. 36 (11): 2120–4. doi:10.1016/j.biocel.2003.11.008. PMID15313458.
