Скаффолд-белки семейства IQGAP – мультифункциональные регуляторы внутриклеточной сигнализации и опухолевой трансформации

Скаффолд-белки, координирующие формирование многокомпонентных белковых комплексов, участвуют в передаче клеточных сигналов по многим сигнальным путям и поэтому являются важными регуляторами клеточных свойств. Белки семейства активаторов гуанозинтрифосфатаз, содержащих IQ-мотивы (IQ Motif Containing GTPase Activating Protein, IQGAP), – многообещающие объекты для исследования роли скаффолд-белков в регуляции внутриклеточной сигнализации и развитии онкологических и других заболеваний. Это семейство включает 3 белка (IQGAP1, IQGAP2 и IQGAP3), обладающие выраженными различиями в спектрах экспрессии и выполняемых функциях. Для всех 3 представителей семейства IQGAP описаны характерные геномные нарушения и изменения экспрессии в различных опухолях. В настоящем обзоре детально рассмотрены строение белков семейства IQGAP, их участие в регуляции клеточных характеристик и взаимодействие с компонентами внутриклеточных сигнальных каскадов. Особое внимание уделено наиболее современным данным о нарушениях функции генов IQGAP в различных типах опухолей и анализу их возможной роли в опухолевой прогрессии, а также их связи с клинико-патологическими характеристиками опухолей.

скаффолд-белки, IQGAP, мультибелковый комплекс, MAP-киназный каскад, сигнальный путь Wnt, β-катенин, опухолевая прогрессия, протоонкоген, опухолевый супрессор

1. Good M.C., Zalatan J.G., Lim W.A. Scaffold proteins: hubs for controlling the flow of cellular information. Science 2011;332(6030):680–6.

2. Krausova M., Korinek V. Wnt-signaling in adult intestinal stem cells and cancer. Cell Signal 2014;26(3):570–9.

3. Singh M., Cowell L., Seo S. et al. Molecular basis for HEF1/NEDD9/Cas-L action as a multifunctional co-ordinator of invasion, apoptosis and cell cycle. Cell Biochem Biophys 2007;48(1):54–72.

4. Smith J.M., Hedman A.C., Sacks D.B. IQGAPs choreograph cellular signaling from the membrane to the nucleus. Trends Cell Biol 2015;25(3):171–84.

5. Wang S., Watanabe T., Noritake J. et al. IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth. J Cell Sci 2007;120(Pt 4):567–77.

6. Интернет-сервис NCBI Gene. https://www.ncbi.nlm.nih.gov/gene. [Internet service NCBI Gene. https://www.ncbi.nlm. nih.gov/gene. (In Russ.)].

7. White C.D., Brown M.D., Sacks D.B. IQGAPs in cancer: a family of scaffold proteins underlying tumorigenesis. FEBS Lett 2009;583(12):1817–24.

8. Umemoto R., Nishida N., Ogino S., Shimada I. NMR structure of the calponin homology domain of human IQGAP1 and its implications for the actin recognition mode. J Biomol NMR 2010;48(1):59–64.

9. Yang Y., Zhao W., Xu Q.W. et al. IQGAP3 promotes EGFR-ERK signaling and the growth and metastasis of lung cancer cells. PLoS One 2014;9(5):e97578.

10. Vetterkind S., Poythress R.H., Lin Q.Q., Morgan K.G. Hierarchical scaffolding of an ERK1/2 activation pathway. Cell Commun Signal 2013;11:65.

11. Pathmanathan S., Hamilton E., Atcheson E., Timson D.J. The interaction of IQGAPs with calmodulin-like proteins. Biochem Soc Trans 2011;39(2):694–9.

12. Atcheson E., Hamilton E., Pathmanathan S. et al. IQ-motif selectivity in human IQGAP2 and IQGAP3: binding of calmodulin and myosin essential light chain. Biosci Rep 2011;31(5):371–9.

13. Kurella V.B., Richard J.M., Parke C.L. et al. Crystal structure of the GTPase-activating protein-related domain from IQGAP1. J Biol Chem 2009;284(22):14857–65.

14. Schmidt V.A. Watch the GAP: emerging roles for IQ motif-containing GTPase-activating proteins IQGAPs in hepatocellular carcinoma. Int J Hepatol 2012;2012:958673.

15. Dixon M.J., Gray A., Schenning M. et al. IQGAP proteins reveal an atypical phosphoinositide (aPI) binding domain with a pseudo C2 domain fold. J Biol Chem 2012;287(27):22483–96.

16. Li Z., Kim S.H., Higgins J.M. et al. IQGAP1 and calmodulin modulate E-cadherin function. J Biol Chem 1999;274(53):37885–92.

17. Watanabe T., Wang S., Kaibuchi K. IQGAPs as key regulators of actin-cytoskeleton dynamics. Cell Struct Funct 2015;40(2):69–77.

18. Noritake J., Watanabe T., Sato K. et al. IQGAP1: a key regulator of adhesion and migration. J Cell Sci 2005;118(Pt 10): 2085–92.

19. Rittmeyer E.N., Daniel S., Hsu S.C., Osman M.A. A dual role for IQGAP1 in regulating exocytosis. J Cell Sci 2008;121(Pt 3):391–403.

20. Sakurai-Yageta M., Recchi C., Le Dez G. et al. The interaction of IQGAP1 with the exocyst complex is required for tumor cell invasion downstream of CDC42 and RHOA. J Cell Biol 2008;181(6):985–98.

21. Schmidt V.A., Scudder L., Devoe C.E. et al. IQGAP2 functions as a GTP-dependent effector protein in thrombin-induced platelet cytoskeletal reorganization. Blood 2003;101(8):3021–8.

22. Vaitheesvaran B., Hartil K., Navare A. et al. Role of the tumor suppressor IQGAP2 in metabolic homeostasis: Possible link between diabetes and cancer. Metabolomics 2014;10(5):920–37.

23. Ghaleb A.M., Bialkowska A.B., Snider A.J. et al. IQ Motif-containing GTPaseactivating protein 2(IQGAP2) is a novel regulator of colonic inflammation in mice. PloS One 2015;10(6):e0129314.

24. Kunimoto K., Nojima H., Yamazaki Y. et al. Involvement of IQGAP3, a regulator of Ras/ERK-related cascade, in hepatocyte proliferation in mouse liver regeneration and development. J Cell Physiol 2009;220(3):621–31.

25. Nojima H., Adachi M., Matsui T. et al. IQGAP3 regulates cell proliferation through the Ras/ERK signalling cascade. Nat Cell Biol 2008;10(8):971–8.

26. Wu Y., Chen Y.C. Structure and function of IQ-domain GTPase-activating protein 1 and its association with tumor progression. Biomed Rep 2014;2(1):3–6.

27. Goto T., Sato A., Shimizu M. et al. IQGAP1 functions as a modulator of dishevelled nuclear localization in Wnt signaling. PLoS One 2013;8(4):e60865.

28. Schmidt V.A., Chiariello C.S., Capilla E. et al. Development of hepatocellular carcinoma in Iqgap2-deficient mice is IQGAP1 dependent. Mol Cell Biol 2008;28(5):1489–502.

29. Carmon K.S., Gong X., Yi J. et al. RSPOLGR4 functions via IQGAP1 to potentiate Wnt signaling. Proc Natl Acad Sci USA 2014;111(13):1221–9.

30. Jacquemet G., Humphries M.J. IQGAP1 is a key node within the small GTPase network. Small GTPases 2013;4(4): 199–207.

31. Adachi M., Kawasaki A., Nojima H. et al. Involvement of IQGAP family proteins in the regulation of mammalian cell cytokinesis. Genes Cells 2014;19(11):803–20.

32. Bañón-Rodríguez I., Gálvez-Santisteban M., Vergarajauregui S. et al. EGFR controls IQGAP basolateral membrane localization and mitotic spindle orientation during epithelial morphogenesis. EMBO J 2014;33(2):129–45.

33. Erdemir H.H., Li Z., Sacks D.B. IQGAP1 binds to estrogen receptor-α and modulates its function. J Biol Chem 2014;289(13):9100–12.

34. Chen F., Zhu H.H., Zhou L.F. et al. IQGAP1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation by Akt activation. Exp Mol Med 2010;42(7):477–83.

35. White C.D., Khurana H., Gnatenko D.V. et al. IQGAP1 and IQGAP2 are reciprocally altered in hepatocellular carcinoma. BMC Gastroenterol 2010;10:125.

36. Jin X., Liu Y., Liu J. et al. The overexpression of IQGAP1 and β-catenin is associated with tumor progression in hepatocellular carcinoma in vitro and in vivo. PLoS One 2015;10(8):e0133770.

37. Meng D., Wu W., Li Z., Qin G. IQGAP1 modulates the proliferation and invasion of thyroid cancer cells in response to estrogen. Int J Mol Med 2015;36(2):588–94.

38. Walch A., Seidl S., Hermannstädter C. et al. Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer. Mod Pathol 2008;21(5):544–52.

39. Takemoto H., Doki Y., Shiozaki H. et al. Localization of IQGAP1 is inversely correlated with intercellular adhesion mediated by E-cadherin in gastric cancers. Int J Cancer 2001;91(6):783–8.

40. Jadeski L., Mataraza J.M., Jeong H.W. et al. IQGAP1 stimulates proliferation and enhances tumorigenesis of human breast epithelial cells. J Biol Chem 2008;283(2):1008–17.

41. Monteleon C.L., McNeal A., Duperret E.K. et al. IQGAP1 and IQGAP3 serve individually essential roles in normal epidermal homeostasis and tumor progression. J Invest Dermatol 2015;135(9):2258–65.

42. Nabeshima K., Shimao Y., Inoue T., Koono M. Immunohistochemical analysis of IQGAP1 expression in human colorectal carcinomas: its overexpression in carcinomas and association with invasion fronts. Cancer Lett 2002;176(1):101–9.

43. Dong P.X., Jia N., Xu Z.J. et al. Silencing of IQGAP1 by shRNA inhibits the invasion of ovarian carcinoma HO-8910PM cells in vitro. J Exp Clin Cancer Res 2008;27:77.

44. Patel V., Hood B.L., Molinolo A.A. et al. Proteomic analysis of laser-captured paraffin-embedded tissues: a molecular portrait of head and neck cancer progression. Clin Cancer Res 2008;14(4):1002–14.

45. Gao J., Aksoy B.A., Dogrusoz U. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;6(269):pl1.

46. Cerami E., Gao J., Dogrusoz U. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2012;2(5):401–4.

47. Gnatenko D.V., Xu X., Zhu W., Schmidt V.A. Transcript profiling identifies Iqgap2 – /– mouse as a model for advanced human hepatocellular carcinoma. PLoS One 2013;8(8):e71826.

48. Jin S.H., Akiyama Y., Fukamachi H. et al. IQGAP2 inactivation through aberrant promoter methylation and promotion of invasion in gastric cancer cells. Int J Cancer 2008;122(5):1040–6.

49. Xie Y., Yan J., Cutz J.C. et al. IQGAP2, a candidate tumour suppressor of prostate tumorigenesis. Biochim Biophys Acta 2012;1822(6):875–84.

50. Xia F.D., Wang Z.L., Chen H.X. et al. Differential expression of IQGAP1/2 in hepatocellular carcinoma and its relationship with clinical outcomes. Asian Pac J Cancer Prev 2014;15(12):4951–6.

51. Zoheir K.M., Abd-Rabou A.A., Harisa G.I. et al. Gene expression of IQGAPs and Ras families in an experimental mouse model for hepatocellular carcinoma: a mechanistic study of cancer progression. Int J Clin Exp Pathol 2015;8(8):8821–31.

52. Zoheir K.M., Abd-Rabou A.A., Harisa G.I. et al. IQGAP1 gene silencing induces apoptosis and decreases the invasive capacity of human hepatocellular carcinoma cells. Tumor Biol 2016;37(10):13927–39.

53. Wu K., Zhang X., Li F. et al. Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas. Nat Commun 2015;6:10131.

54. Jameson K.L., Mazur P.K., Zehnder A.M. et al. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors. Nat Med 2013;19(5):626–30.