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Caspase-mediated cleavage of the TIAM1 guanine nucleotide exchange factor during apoptosis. 总被引:3,自引:0,他引:3
H Qi P Juo J Masuda-Robens M J Caloca H Zhou N Stone M G Kazanietz M M Chou 《Cell growth & differentiation》2001,12(12):603-611
Rho family GTPases Rac and Cdc42 are pivotal regulators of apoptosis in multiple cell types. However, little is known about the mechanism by which these GTPases are regulated in response to apoptotic stimuli. Here, we demonstrate that TIAM1, a Rac-specific guanine nucleotide exchange factor, is cleaved by caspases during apoptosis. TIAM1 cleavage occurs in multiple cell lines in response to diverse apoptotic stimuli such as ceramide, Fas, and serum deprivation. Processing occurs at residue 993 of TIAM1 and removes the NH(2)-terminal of TIAM's two pleckstrin homology domains, leaving a stable fragment containing the Dbl homology and COOH-terminal pleckstrin homology domains. This leads to functional inactivation of TIAM1, as determined by failure of the cleavage product to stimulate GTP loading of Rac in vivo. Furthermore, this product is defective in signaling to two independent Rac effectors, c-Jun NH(2)-terminal kinase and serum response factor. Finally, we demonstrate that in cells treated with ceramide, cleavage of TIAM1 coincided with the inactivation of endogenous Rac. These results reveal a novel mechanism for regulating guanine nucleotide exchange factor activity and GTPase-mediated signaling pathways. 相似文献
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Yang Y Li L Wong GW Krilis SA Madhusudhan MS Sali A Stevens RL 《The Journal of biological chemistry》2002,277(28):25756-25774
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Dirks RP Potter SJ Griep AE 《Biochemical and biophysical research communications》2001,287(4):900-909
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Yangyang Yue Kaijie Wu Weikun Qian Zeen Zhu Simei Zhang Wunai Zhang Weifan Zhang Shuai Wu Li Li Zheng Wu Qingyong Ma Keping Xie Zheng Wang 《International journal of biological sciences》2022,18(10):4245
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high incidence of metastasis and dismal prognosis. As a member of Gas-Gap gene, RASAL2 is involved in the hydrolysis of RAS-GTP to RAS-GDP and abnormal expression in human cancers. Here we firstly described the function of RASAL2 on PDAC to enrich the knowledge of RAS family.We interestingly observed that RASAL2 expression was upregulated in PDAC at both mRNA and protein levels, and high expression of RASAL2 predicted a poor prognosis in PDAC patients. Additionally, RASAL2 promoted malignant behaviors of PDAC in vitro and in vivo. To determine the mechanistic roles of RASAL2 signaling and its potential as a therapeutic target in PDAC, we clarified that RASAL2 could accumulate the TIAM1 expression in different level through inhibiting YAP1 phosphorylation, increased TIAM1 mRNA expression and suppressed ubiquitination of TIAM1 protein. In conclusion, RASAL2 enhances YAP1/TIAM1 signaling and promotes PDAC development and progression. 相似文献
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Corpe CP Bovelander FJ Munoz CM Hoekstra JH Simpson IA Kwon O Levine M Burant CF 《Biochimica et biophysica acta》2002,1576(1-2):191-197
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