AKT1

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AKT1, do inglês V-akt murine thymoma viral oncogene homolog 1, é uma enzima que em humanos é codificada pelo gene AKT1.

A proteína quinase serina/treonina codificada pelo gene AKT1 está cataliticamente inactiva em fibroblastos privados de soro e em fibroblastos imortalizados. AKT1 e o ATK2 são activados por factores de crescimento derivados de plaquetas. A activação é rápida e específica, não sendo anulada por mutações no domínio de homologia a plecstrina da AKT1. Foi demonstrado que a activação ocorre através do fosfoinositol 3-quinase.

No sistema nervoso em desenvolvimento, o AKT é um mediador crítico da sobrevivência neuronal induzida por factores de crescimento. Os factores de crescimento podem suprimir a apoptose de uma maneira independete de transcrição, por activação da quinase serina/treonina AKT1, que depois fosforila e inactiva componentes da apoptose.

Múltiplos variantes de transcriptos, que sofreram splicing alternativo, foram encontrados para este gene. [1]

Ratos que não possuem AKT1 mostram uma redução em 25% da massa corporal, indicando que este gene é fundamental para que os sinais dos factores de crescimento sejam transmitidos, mais provavelmente através do receptor IGF1. Os ratos que não possuem AKT1 são também resistentes ao cancro: apresentam atrasos consideráveis no crescimento de tumores iniciados, por exemplo pelo oncogene NEU.

Interações[editar | editar código-fonte]

AKT1 mostrou interação com Phosphoinositide-dependent kinase-1,[2] [3] Keratin 10,[4] Integrin-linked kinase,[2] [5] [3] TSC2,[6] [7] GAB2,[8] TRIB3,[9] NPM1,[10] BRCA1,[11] [12] BRAF,[13] C-Raf,[14] MAPK14,[15] MARK2,[16] MAP2K4,[17] MTCP1,[18] [19] TCL1A,[18] [19] [20] Nerve Growth factor IB,[21] MAPKAPK2,[15] PRKCQ,[22] Androgen receptor,[23] Heat shock protein 90kDa alpha (cytosolic), member A1,[24] [25] [26] Plexin A1,[27] MAP3K11,[28] TSC1,[7] [6] MAP3K8,[29] Mammalian target of rapamycin,[30] [31] [32] PKN2,[33] AKTIP,[34] YWHAZ,[35] CHUK[36] [37] e CDKN1B.[38]

Referências[editar | editar código-fonte]

  1. Entrez Gene: AKT1 v-akt murine thymoma viral oncogene homolog 1.
  2. a b Barry, Fiona A; Gibbins Jonathan M. (Apr. 2002). "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". J. Biol. Chem. 277 (15): 12874–8. DOI:10.1074/jbc.M200482200. ISSN 0021-9258. PMID 11825911.
  3. a b Persad, S; Attwell S, Gray V, Mawji N, Deng J T, Leung D, Yan J, Sanghera J, Walsh M P, Dedhar S. (Jul. 2001). "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343". J. Biol. Chem. 276 (29): 27462–9. DOI:10.1074/jbc.M102940200. ISSN 0021-9258. PMID 11313365.
  4. Paramio, J M; Segrelles C, Ruiz S, Jorcano J L. (Nov. 2001). "Inhibition of protein kinase B (PKB) and PKCzeta mediates keratin K10-induced cell cycle arrest". Mol. Cell. Biol. 21 (21): 7449–59. DOI:10.1128/MCB.21.21.7449-7459.2001. ISSN 0270-7306. PMID 11585925.
  5. Delcommenne, M; Tan C, Gray V, Rue L, Woodgett J, Dedhar S. (Sep. 1998). "Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase". Proc. Natl. Acad. Sci. U.S.A. 95 (19): 11211–6. DOI:10.1073/pnas.95.19.11211. ISSN 0027-8424. PMID 9736715.
  6. a b Dan, Han C; Sun Mei, Yang Lin, Feldman Richard I, Sui Xue-Mei, Ou Chien Chen, Nellist Mark, Yeung Raymond S, Halley Dicky J J, Nicosia Santo V, Pledger Warren J, Cheng Jin Q. (Sep. 2002). "Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin". J. Biol. Chem. 277 (38): 35364–70. DOI:10.1074/jbc.M205838200. ISSN 0021-9258. PMID 12167664.
  7. a b Roux, Philippe P; Ballif Bryan A, Anjum Rana, Gygi Steven P, Blenis John. (Sep. 2004). "Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase". Proc. Natl. Acad. Sci. U.S.A. 101 (37): 13489–94. DOI:10.1073/pnas.0405659101. ISSN 0027-8424. PMID 15342917.
  8. Lynch, Danielle K; Daly Roger J. (Jan. 2002). "PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2". EMBO J. 21 (1-2): 72–82. DOI:10.1093/emboj/21.1.72. ISSN 0261-4189. PMID 11782427.
  9. Du, Keyong; Herzig Stephan, Kulkarni Rohit N, Montminy Marc. (Jun. 2003). "TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver". Science 300 (5625): 1574–7. DOI:10.1126/science.1079817. PMID 12791994.
  10. Lee, Sang Bae; Xuan Nguyen Truong L, Choi Joung Woo, Lee Kyung-Hoon, Cho Sung-Woo, Liu Zhixue, Ye Keqiang, Bae Sun Sik, Ahn Jee-Yin. (Oct. 2008). "Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival". Proc. Natl. Acad. Sci. U.S.A. 105 (43): 16584–9. DOI:10.1073/pnas.0807668105. PMID 18931307.
  11. Altiok, S; Batt D, Altiok N, Papautsky A, Downward J, Roberts T M, Avraham H. (Nov. 1999). "Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells". J. Biol. Chem. 274 (45): 32274–8. DOI:10.1074/jbc.274.45.32274. ISSN 0021-9258. PMID 10542266.
  12. Xiang, Tao; Ohashi Amiko, Huang Yuping, Pandita Tej K, Ludwig Thomas, Powell Simon N, Yang Qin. (Dec. 2008). "Negative Regulation of AKT Activation by BRCA1". Cancer Res. 68 (24): 10040–4. DOI:10.1158/0008-5472.CAN-08-3009. PMID 19074868.
  13. Guan, K L; Figueroa C, Brtva T R, Zhu T, Taylor J, Barber T D, Vojtek A B. (Sep. 2000). "Negative regulation of the serine/threonine kinase B-Raf by Akt". J. Biol. Chem. 275 (35): 27354–9. DOI:10.1074/jbc.M004371200. ISSN 0021-9258. PMID 10869359.
  14. Zimmermann, S; Moelling K. (Nov. 1999). "Phosphorylation and regulation of Raf by Akt (protein kinase B)". Science 286 (5445): 1741–4. DOI:10.1126/science.286.5445.1741. ISSN 0036-8075. PMID 10576742.
  15. a b Rane, M J; Coxon P Y, Powell D W, Webster R, Klein J B, Pierce W, Ping P, McLeish K R. (Feb. 2001). "p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils". J. Biol. Chem. 276 (5): 3517–23. DOI:10.1074/jbc.M005953200. ISSN 0021-9258. PMID 11042204.
  16. Dickey, Chad A; Koren John, Zhang Yong-Jie, Xu Ya-Fei, Jinwal Umesh K, Birnbaum Morris J, Monks Bobby, Sun Mei, Cheng Jin Q, Patterson Cam, Bailey Rachel M, Dunmore Judith, Soresh Sareh, Leon Carlos, Morgan Dave, Petrucelli Leonard. (Mar. 2008). "Akt and CHIP coregulate tau degradation through coordinated interactions". Proc. Natl. Acad. Sci. U.S.A. 105 (9): 3622–7. DOI:10.1073/pnas.0709180105. PMID 18292230.
  17. Park, Hee-Sae; Kim Mi-Sung, Huh Sung-Ho, Park Jihyun, Chung Jongkyeong, Kang Sang Sun, Choi Eui-Ju. (Jan. 2002). "Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation". J. Biol. Chem. 277 (4): 2573–8. DOI:10.1074/jbc.M110299200. ISSN 0021-9258. PMID 11707464.
  18. a b Laine, Jarmo; Künstle Gerald, Obata Toshiyuki, Noguchi Masayuki. (Feb. 2002). "Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family". J. Biol. Chem. 277 (5): 3743–51. DOI:10.1074/jbc.M107069200. ISSN 0021-9258. PMID 11707444.
  19. a b Laine, J; Künstle G, Obata T, Sha M, Noguchi M. (Aug. 2000). "The protooncogene TCL1 is an Akt kinase coactivator". Mol. Cell 6 (2): 395–407. DOI:10.1016/S1097-2765(00)00039-3. ISSN 1097-2765. PMID 10983986.
  20. French, Samuel W; Shen Rhine R, Koh Patricia J, Malone Cindy S, Mallick Parag, Teitell Michael A. (May. 2002). "A modeled hydrophobic domain on the TCL1 oncoprotein mediates association with AKT at the cytoplasmic membrane". Biochemistry 41 (20): 6376–82. DOI:10.1021/bi016068o. ISSN 0006-2960. PMID 12009899.
  21. Pekarsky, Y; Hallas C, Palamarchuk A, Koval A, Bullrich F, Hirata Y, Bichi R, Letofsky J, Croce C M. (Mar. 2001). "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proc. Natl. Acad. Sci. U.S.A. 98 (7): 3690–4. DOI:10.1073/pnas.051003198. ISSN 0027-8424. PMID 11274386.
  22. Bauer, B; Krumböck N, Fresser F, Hochholdinger F, Spitaler M, Simm A, Uberall F, Schraven B, Baier G. (Aug. 2001). "Complex formation and cooperation of protein kinase C theta and Akt1/protein kinase B alpha in the NF-kappa B transactivation cascade in Jurkat T cells". J. Biol. Chem. 276 (34): 31627–34. DOI:10.1074/jbc.M103098200. ISSN 0021-9258. PMID 11410591.
  23. Lin, H K; Yeh S, Kang H Y, Chang C. (Jun. 2001). "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor". Proc. Natl. Acad. Sci. U.S.A. 98 (13): 7200–5. DOI:10.1073/pnas.121173298. ISSN 0027-8424. PMID 11404460.
  24. Haendeler, Judith; Hoffmann Jörg, Rahman Sandy, Zeiher Andreas M, Dimmeler Stefanie. (Feb. 2003). "Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation". FEBS Lett. 536 (1-3): 180–6. DOI:10.1016/S0014-5793(03)00058-9. ISSN 0014-5793. PMID 12586360.
  25. Kawauchi, Kiyotaka; Ihjima Kimiko, Yamada Osamu. (May. 2005). "IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells". J. Immunol. 174 (9): 5261–9. ISSN 0022-1767. PMID 15843522.
  26. Sato, S; Fujita N, Tsuruo T. (Sep. 2000). "Modulation of Akt kinase activity by binding to Hsp90". Proc. Natl. Acad. Sci. U.S.A. 97 (20): 10832–7. DOI:10.1073/pnas.170276797. ISSN 0027-8424. PMID 10995457.
  27. Turner, Laura J; Nicholls Sarah, Hall Alan. (Aug. 2004). "The activity of the plexin-A1 receptor is regulated by Rac". J. Biol. Chem. 279 (32): 33199–205. DOI:10.1074/jbc.M402943200. ISSN 0021-9258. PMID 15187088.
  28. Barthwal, Manoj K; Sathyanarayana Pradeep, Kundu Chanakya N, Rana Basabi, Pradeep Anamika, Sharma Chandan, Woodgett James R, Rana Ajay. (Feb. 2003). "Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival". J. Biol. Chem. 278 (6): 3897–902. DOI:10.1074/jbc.M211598200. ISSN 0021-9258. PMID 12458207.
  29. Kane, Lawrence P; Mollenauer Marianne N, Xu Zheng, Turck Christoph W, Weiss Arthur. (Aug. 2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Mol. Cell. Biol. 22 (16): 5962–74. DOI:10.1128/MCB.22.16.5962-5974.2002. ISSN 0270-7306. PMID 12138205.
  30. Sarbassov, D D; Guertin David A, Ali Siraj M, Sabatini David M. (Feb. 2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science 307 (5712): 1098–101. DOI:10.1126/science.1106148. PMID 15718470.
  31. Sekulić, A; Hudson C C, Homme J L, Yin P, Otterness D M, Karnitz L M, Abraham R T. (Jul. 2000). "A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells". Cancer Res. 60 (13): 3504–13. ISSN 0008-5472. PMID 10910062.
  32. Cheng, Susan W Y; Fryer Lee G D, Carling David, Shepherd Peter R. (Apr. 2004). "Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status". J. Biol. Chem. 279 (16): 15719–22. DOI:10.1074/jbc.C300534200. ISSN 0021-9258. PMID 14970221.
  33. Koh, H; Lee K H, Kim D, Kim S, Kim J W, Chung J. (Nov. 2000). "Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage". J. Biol. Chem. 275 (44): 34451–8. DOI:10.1074/jbc.M001753200. ISSN 0021-9258. PMID 10926925.
  34. Remy, Ingrid; Michnick Stephen W. (Feb. 2004). "Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt". Mol. Cell. Biol. 24 (4): 1493–504. DOI:10.1128/MCB.24.4.1493-1504.2004. ISSN 0270-7306. PMID 14749367.
  35. Powell, David W; Rane Madhavi J, Chen Qingdan, Singh Saurabh, McLeish Kenneth R. (Jun. 2002). "Identification of 14-3-3zeta as a protein kinase B/Akt substrate". J. Biol. Chem. 277 (24): 21639–42. DOI:10.1074/jbc.M203167200. ISSN 0021-9258. PMID 11956222.
  36. Ozes, O N; Mayo L D, Gustin J A, Pfeffer S R, Pfeffer L M, Donner D B. (Sep. 1999). "NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase". Nature 401 (6748): 82–5. DOI:10.1038/43466. ISSN 0028-0836. PMID 10485710.
  37. Romashkova, J A; Makarov S S. (Sep. 1999). "NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling". Nature 401 (6748): 86–90. DOI:10.1038/43474. ISSN 0028-0836. PMID 10485711.
  38. Fujita, Naoya; Sato Saori, Katayama Kazuhiro, Tsuruo Takashi. (Aug. 2002). "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization". J. Biol. Chem. 277 (32): 28706–13. DOI:10.1074/jbc.M203668200. ISSN 0021-9258. PMID 12042314.

Leitura adicional[editar | editar código-fonte]

  • Hemmings BA. (1997). "Akt signaling: linking membrane events to life and death decisions.". Science 275 (5300): 628-30. PMID 9019819.
  • Vanhaesebroeck B, Alessi DR. (2000). "The PI3K-PDK1 connection: more than just a road to PKB.". Biochem. J. 346 Pt 3: 561-76. PMID 10698680.
  • Chan TO, Rittenhouse SE, Tsichlis PN. (2000). "AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation.". Annu. Rev. Biochem. 68: 965-1014. DOI:10.1146/annurev.biochem.68.1.965. PMID 10872470.
  • Pekarsky Y, Hallas C, Croce CM. (2001). "Molecular basis of mature T-cell leukemia.". JAMA 286 (18): 2308-14. PMID 11710897.
  • Dickson LM, Rhodes CJ. (2004). "Pancreatic beta-cell growth and survival in the onset of type 2 diabetes: a role for protein kinase B in the Akt?". Am. J. Physiol. Endocrinol. Metab. 287 (2): E192-8. DOI:10.1152/ajpendo.00031.2004. PMID 15271644.
  • Manning BD. (2004). "Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis.". J. Cell Biol. 167 (3): 399-403. DOI:10.1083/jcb.200408161. PMID 15533996.
  • Shinohara M, Chung YJ, Saji M, Ringel MD. (2007). "AKT in thyroid tumorigenesis and progression.". Endocrinology 148 (3): 942-7. DOI:10.1210/en.2006-0937. PMID 16946008.

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