Kindlin Signaling and Bone

Abstract

In mammals, the Kindlin family consists of three evolutionarily conserved members, Kindlin-1, -2, and -3. The major function of Kindlins is to activate integrin through direct binding to the β-integrin cytoplasmic tails, which requires the cooperation with talin, a large cytoplasmic adaptor protein. Through integrin activation, Kindlins regulate several fundamental aspects of cells, such as cell–extracellular matrix (ECM) adhesion and migration, cell survival, proliferation and differentiation. Kindlins also modulate cytoskeletal remodeling through direct or indirect interaction with actin and other proteins. Cumulative evidence suggests important integrin-independent functions of Kindlins under physiological and pathological conditions. In this chapter, we first review basic aspects of Kindlins, including their tissue expression patterns and protein structures, and two human genetic diseases due to gene mutations of KINDLINs, followed by a discussion about the roles of Kindlin signaling in regulation of integrin activation and cytoskeletal reorganization. We then discuss recent advances on integrin independent functions of Kindlins by focusing on their interactions with other key signaling molecules, including β-catenin, TGFR/Smads, EGFR, and Rac1. Finally, we discuss the roles of Kindlins in bone, with a special focus on recently defined roles and mechanisms of Kindlin-2 in control of mesenchymal stem cell differentiation and skeletal development.