The long-term goal of this competing renewal application is to elucidate the molecular basis underlying cell- extracellular matrix (ECM) adhesion and regulation, and the mechanism whereby they control cell behavior, tissue integrity, growth and regeneration. Recent studies by the applicant and others have demonstrated a critical role of kindlin-2 (also known as Mig-2), a widely expressed membrane-cytoskeleton junctional protein, in integrin activation and cell-ECM adhesion. How kindlin-2 regulates these processes, however, is not known. Based on findings obtained during previous project periods, the applicant hypothesizes that kindlin-2 regulates these processes through interacting with membrane lipids and protein components of cell-ECM adhesions. To test this hypothesis, he proposes studies with the following three aims.
Aim 1 is to characterize the interaction of kindlin-2 with membrane lipids and assess its role in regulation of integrins and integrin-dependent processes. To this end, he will employ genetic, pharmacological and dominant negative inhibition strategies to ablate this interaction, and determine the consequences.
Aim 2 is to determine the functions of kindlin-2 interactions with focal adhesion proteins in regulation of cell-ECM adhesion. He will define the sites mediating the interactions and use a """"""""knock-in"""""""" strategy to replace wild type kindlin-2 with mutants lacking specific protein-binding activity and determine the consequences.
Aim 3 is to investigate the functions of kindlin-2 and its interplay with ILK in liver structure, growth and regeneration, which are known to be regulated by ECM adhesion and ILK signaling. He will generate hepatocyte-specific kindlin-2 knockout and """"""""knock-in"""""""" mice, in which wild type kindlin-2 is substituted with kindlin-2 mutants lacking specific binding activities, and determine contributions of kindlin-2 and its interactions to regulation of hepatocyte behavior, liver structure, growth and regeneration. These studies will fill important gaps in our understanding of the mechanism whereby cell-ECM adhesion and ECM-dependent tissue processes are regulated. Given the importance of cell-ECM adhesion in human diseases, these studies may also lead to novel approaches to control diseases associated with abnormal cell-ECM adhesion and signaling.
Alteration of cell-ECM adhesion is critically involved in the pathogenesis of human diseases including cancer. This project seeks to determine how a recently identified regulator of cell-ECM adhesion influences cell-ECM adhesion, tissue structure, growth and regeneration. These studies may lead to identification of novel therapeutic targets to control diseases associated with abnormal cell-ECM adhesion and growth.
|Zhu, Ke; Yi, Jianxun; Xiao, Yajuan et al. (2015) Impaired bone homeostasis in amyotrophic lateral sclerosis mice with muscle atrophy. J Biol Chem 290:8081-94|
|Wu, Chuanyue; Jiao, Hongli; Lai, Yumei et al. (2015) Kindlin-2 controls TGF-? signalling and Sox9 expression to regulate chondrogenesis. Nat Commun 6:7531|
|Liu, Z; Zhan, Y; Tu, Y et al. (2015) PDZ and LIM domain protein 1(PDLIM1)/CLP36 promotes breast cancer cell migration, invasion and metastasis through interaction with ?-actinin. Oncogene 34:1300-11|
|Qu, Hong; Tu, Yizeng; Guan, Jun-Lin et al. (2014) Kindlin-2 tyrosine phosphorylation and interaction with Src serve as a regulatable switch in the integrin outside-in signaling circuit. J Biol Chem 289:31001-13|
|Song, Chenlin; Zhu, Songcheng; Wu, Chuanyue et al. (2013) Histone deacetylase (HDAC) 10 suppresses cervical cancer metastasis through inhibition of matrix metalloproteinase (MMP) 2 and 9 expression. J Biol Chem 288:28021-33|
|Gkretsi, Vasiliki; Papanikolaou, Vassilis; Dubos, Stephanie et al. (2013) Migfilin's elimination from osteoarthritic chondrocytes further promotes the osteoarthritic phenotype via ?-catenin upregulation. Biochem Biophys Res Commun 430:494-9|
|Davidson, Ben; Holth, Arild; Nguyen, Mai T P et al. (2013) Migfilin, ýý-parvin and ýý-parvin are differentially expressed in ovarian serous carcinoma effusions, primary tumors and solid metastases. Gynecol Oncol 128:364-70|
|Xiao, Guozhi; Cheng, Hongqiang; Cao, Huiling et al. (2012) Critical role of filamin-binding LIM protein 1 (FBLP-1)/migfilin in regulation of bone remodeling. J Biol Chem 287:21450-60|
|Qin, Jun; Wu, Chuanyue (2012) ILK: a pseudokinase in the center stage of cell-matrix adhesion and signaling. Curr Opin Cell Biol 24:607-13|
|Liu, Jianmin; Fukuda, Koichi; Xu, Zhen et al. (2011) Structural basis of phosphoinositide binding to kindlin-2 protein pleckstrin homology domain in regulating integrin activation. J Biol Chem 286:43334-42|
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