Kindlin-2 modulates MafA and β-catenin expression to regulate β-cell function and mass in mice

Ke Zhu; Yumei Lai; Huiling Cao; Xiaochun Bai; Chuanju Liu; Qinnan Yan; Liting Ma; Di Chen; Giedrius Kanaporis; Junqi Wang; Luyuan Li; Tao Cheng; Yong Wang; Chuanyue Wu; Guozhi Xiao

doi:10.1038/s41467-019-14186-y

Kindlin-2 modulates MafA and β-catenin expression to regulate β-cell function and mass in mice

Nat Commun. 2020 Jan 24;11(1):484. doi: 10.1038/s41467-019-14186-y.

Authors

Ke Zhu¹, Yumei Lai¹, Huiling Cao², Xiaochun Bai³, Chuanju Liu^{4

5}, Qinnan Yan², Liting Ma², Di Chen¹, Giedrius Kanaporis⁶, Junqi Wang², Luyuan Li⁷, Tao Cheng⁸, Yong Wang⁹, Chuanyue Wu¹⁰, Guozhi Xiao^{11

12}

Affiliations

¹ Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA.
² Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, and Department of Biology, Southern University of Science and Technology, 518055, Shenzhen, China.
³ Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, 510515, Guangzhou, China.
⁴ Department of Orthopedic Surgery, New York University School of Medicine, New York, NY, 10003, USA.
⁵ Department of Cell Biology, New York University School of Medicine, New York, NY, 10016, USA.
⁶ Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, 60612, USA.
⁷ State Key Laboratory of Medicinal Chemical Biology and Nankai University College of Pharmacy, 300071, Tianjin, China.
⁸ State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, 300020, Tianjin, China.
⁹ UVA Islet Microfluidic Laboratory, Department of Surgery, the University of Virginia, Charlottesville, VA, 22908, USA.
¹⁰ Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15261, USA. [email protected].
¹¹ Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, and Department of Biology, Southern University of Science and Technology, 518055, Shenzhen, China. [email protected].
¹² Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL, 60612, USA. [email protected].

Abstract

β-Cell dysfunction and reduction in β-cell mass are hallmark events of diabetes mellitus. Here we show that β-cells express abundant Kindlin-2 and deleting its expression causes severe diabetes-like phenotypes without markedly causing peripheral insulin resistance. Kindlin-2, through its C-terminal region, binds to and stabilizes MafA, which activates insulin expression. Kindlin-2 loss impairs insulin secretion in primary human and mouse islets in vitro and in mice by reducing, at least in part, Ca²⁺ release in β-cells. Kindlin-2 loss activates GSK-3β and downregulates β-catenin, leading to reduced β-cell proliferation and mass. Kindlin-2 loss reduces the percentage of β-cells and concomitantly increases that of α-cells during early pancreatic development. Genetic activation of β-catenin in β-cells restores the diabetes-like phenotypes induced by Kindlin-2 loss. Finally, the inducible deletion of β-cell Kindlin-2 causes diabetic phenotypes in adult mice. Collectively, our results establish an important function of Kindlin-2 and provide a potential therapeutic target for diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Proliferation
Cytoskeletal Proteins / deficiency
Cytoskeletal Proteins / genetics
Cytoskeletal Proteins / metabolism*
Diabetes Mellitus, Experimental / etiology
Diabetes Mellitus, Experimental / metabolism
Diabetes Mellitus, Experimental / pathology
Female
Gene Expression
Gene Knockdown Techniques
Humans
Insulin / genetics
Insulin Resistance
Insulin-Secreting Cells / cytology*
Insulin-Secreting Cells / metabolism*
Islets of Langerhans / growth & development
Islets of Langerhans / metabolism
Maf Transcription Factors, Large / metabolism*
Male
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Muscle Proteins / deficiency
Muscle Proteins / genetics
Muscle Proteins / metabolism*
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Phenotype
Protein Stability
beta Catenin / genetics
beta Catenin / metabolism*

Substances

CTNNB1 protein, mouse
Cytoskeletal Proteins
FERMT2 protein, human
Insulin
Maf Transcription Factors, Large
Mafa protein, mouse
Membrane Proteins
Muscle Proteins
Neoplasm Proteins
beta Catenin
kindlin-2 protein, mouse

Grants and funding

R01 AR068950/AR/NIAMS NIH HHS/United States