Requirement of Gαi1/3-Gab1 Signaling Complex for Keratinocyte Growth Factor-Induced PI3K-AKT-mTORC1 Activation
Requirement of Gαi1/3-Gab1 Signaling Complex for Keratinocyte Growth Factor-Induced PI3K-AKT-mTORC1 Activation
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DOI：
10.1038/jid.2014.326
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发表时间：
2015-01-01
影响因子：
6.5
通讯作者：
Cao, Cong
中科院分区：
文献类型：
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作者：
Zhang, Yi-ming;Zhang, Zhi-qing;Cao, Cong
角质形成细胞生长因子(KGF)，又称成纤维细胞生长因子-7，通过与角质形成细胞生长因子受体(KGFR)结合，进而激活包括PI3K-AKT-nnTORC1通路在内的下游信号通路，促进皮肤角质形成细胞的增殖、迁移和黏附。在这里，我们发现G蛋白的α亚基(Gαi1/3)和生长因子受体结合2相关结合蛋白1(GAB1)是这一激活过程所必需的。在KGF刺激下，Gαil/3与KGFR形成复合体，这是GAB1募集、磷酸化和PI3K-P85激活所必需的。此外，Gαil/3短发夹状RNA基因敲除可显著抑制KGF诱导的皮肤角质形成细胞的增殖、迁移和细胞周期蛋白D1/纤维连接蛋白的积聚。此外，我们观察到GαIL/3在人皮肤创伤和瘢痕疙瘩组织中的表达增加，提示GαIL/3可能参与了伤口愈合和瘢痕疙瘩的形成。总体而言，我们认为GαIL/3蛋白位于KGFR下游，但位于GAB1介导的PI3K-AKT-mTORC1信号通路的上游，从而揭示了GαI蛋白在介导KGFR信号转导、细胞迁移和可能的伤口愈合中的作用。
Keratinocyte growth factor (KGF), also termed as fibroblast growth factor-7, promotes proliferation, migration, and adhesion of skin keratinocytes via binding to keratinocyte growth factor receptor (KGFR) and subsequent activation of downstream signaling including the PI3K-AKT-nnTORC1 pathway. Here, we found that the alpha-subunits of the G proteins (G alpha i1/3) and growth factor receptor binding 2-associated binding protein 1 (Gab1) are required for this activation process. With KGF stimulation, G alpha il/3 formed a complex with KGFR and was required for subsequent Gab1 recruitment, phosphorylation, and following PI3K-p85 activation. In addition, G alpha il/3 short hairpin RNA knockdown largely inhibited KGF-induced cell proliferation, migration, and the accumulation of cyclin D1/fibronectin in cultured skin keratinocytes. Furthermore, we observed increased expression of G alpha il/3 in wounded human skin and keloid skin tissues, suggesting the possible involvement of G alpha il/3 in wound healing and keloid formation. Overall, we suggest that G alpha il/3 proteins lie downstream of KGFR, but upstream of Gab1-mediated activation of PI3K - AKT-mTORC1 signaling, thus revealing a role for G alpha i proteins in mediating KGFR signaling, cell migration, and possible wound healing.