Requirement of Gαi1/3-Gab1 signaling complex for keratinocyte growth factor-induced PI3K-AKT-mTORC1 activation

Yi-Ming Zhang; Zhi-Qing Zhang; Yuan-Yuan Liu; Xin Zhou; Xiao-Hua Shi; Qin Jiang; Dong-Li Fan; Cong Cao

doi:10.1038/jid.2014.326

Requirement of Gαi1/3-Gab1 signaling complex for keratinocyte growth factor-induced PI3K-AKT-mTORC1 activation

J Invest Dermatol. 2015 Jan;135(1):181-191. doi: 10.1038/jid.2014.326. Epub 2014 Jul 31.

Authors

Yi-Ming Zhang¹, Zhi-Qing Zhang², Yuan-Yuan Liu², Xin Zhou¹, Xiao-Hua Shi¹, Qin Jiang³, Dong-Li Fan⁴, Cong Cao⁵

Affiliations

¹ Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
² Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China.
³ The Affiliated Eye Hospital, Nanjing Medical University, Nanjing City, China. Electronic address: Jqin710@vip.sina.com.
⁴ Department of Plastic and Cosmetic Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, China. Electronic address: fdltmmu@sina.com.
⁵ Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and Institute of Neuroscience, Soochow University, Suzhou, China. Electronic address: caocong@suda.edu.cn.

PMID: 25078664
DOI: 10.1038/jid.2014.326

Abstract

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-mTORC1 pathway. Here, we found that the α-subunits of the G proteins (Gαi1/3) and growth factor receptor binding 2-associated binding protein 1 (Gab1) are required for this activation process. With KGF stimulation, Gαi1/3 formed a complex with KGFR and was required for subsequent Gab1 recruitment, phosphorylation, and following PI3K-p85 activation. In addition, Gαi1/3 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 Gαi1/3 in wounded human skin and keloid skin tissues, suggesting the possible involvement of Gαi1/3 in wound healing and keloid formation. Overall, we suggest that Gαi1/3 proteins lie downstream of KGFR, but upstream of Gab1-mediated activation of PI3K-AKT-mTORC1 signaling, thus revealing a role for Gαi proteins in mediating KGFR signaling, cell migration, and possible wound healing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Cell Movement / physiology
Fibroblast Growth Factor 7 / metabolism
GTP-Binding Protein alpha Subunit, Gi2 / genetics
GTP-Binding Protein alpha Subunit, Gi2 / metabolism
GTP-Binding Protein alpha Subunits, Gi-Go / genetics
GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
Gene Knockdown Techniques
HEK293 Cells
Humans
Keloid / genetics
Keloid / metabolism*
Keratinocytes / cytology
Keratinocytes / metabolism*
Mechanistic Target of Rapamycin Complex 1
Multiprotein Complexes / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / physiology
Primary Cell Culture
Proto-Oncogene Proteins c-akt / metabolism
RNA, Small Interfering / genetics
Signal Transduction / physiology*
Skin / cytology
Skin / injuries
Skin / metabolism
TOR Serine-Threonine Kinases / metabolism

Substances

Adaptor Proteins, Signal Transducing
FGF7 protein, human
GAB1 protein, human
Multiprotein Complexes
RNA, Small Interfering
Fibroblast Growth Factor 7
Mechanistic Target of Rapamycin Complex 1
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
GNAI1 protein, human
GNAI2 protein, human
GNAI3 protein, human
GTP-Binding Protein alpha Subunit, Gi2
GTP-Binding Protein alpha Subunits, Gi-Go