Investigating the functions and signaling properties of kindlins

• Main Author: Tan, Hui Foon
• Other Authors: Tan Suet Mien
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2020
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/136978
• Institution: Nanyang Technological University

Kindlins are FERM-containing cytoplasmic proteins that have crucial roles in cell adhesion and migration. The three members kindlin-1, kindlin-2 and kindlin-3 have different tissue expression profiles. The primary role of kindlins is to regulate the activity of integrins by binding directly to β integrin cytoplasmic tails. In this study, we examine the functional properties of kindlin-2 and kindlin-3. We show that kindlin-2 regulates mitotic spindle assembly in the neuroblastoma SH-SY5Y cell line. Mechanistically, it involves the Akt/ GSK3β / Histone deacetylase 6 (HDAC6) or/and Paxillin/ HDAC6 signaling pathway that modulates the acetylation of α-tubulin, a post-translational modification that stabilizes microtubules. Depleting kindlin-2 in cells leads to mitotic spindle abnormalities and delays mitosis. Furthermore, we provide evidence that hypoxia, a hallmark of solid tumour microenvironment, up-regulates miR-138 that suppresses the expression of kindlin-2, leading to spindle abnormalities in cells and slow growth. In a previous study, it has been shown that kindlin-3, but not others, interacts with the scaffold protein RACK1. Here, we identified the specificity determinant in kindlin-3 that is involved in RACK1 interaction. Taken together, our data provide additional insights into the regulatory functions of kindlin-2 and kindlin-3.