Crosstalk between cell adhesion and the actin cytoskeleton

Abstract

In order to form tissues and to move, cells need to attach to the surrounding environment. Integrins are the major cell adhesion receptors that cells use to attach to the extracellular matrix on the outside of the cell, and to recruit a large adhesion complex on the intracellular side. As transmembrane proteins, integrins have an important role in mediating bidirectional signalling across the plasma membrane. Moreover, the integrin-based adhesions are linked to the actin cytoskeleton and thereby act as a link between the extracellular matrix and the actin cytoskeleton. The actin cytoskeleton is responsible for the cellular force generation, and integrin-based adhesions and the actin cytoskeleton create thereby a machinery, that cells can use for example to move. Moreover, integrins and the actin cytoskeleton can mediate reactions to extracellular cues and even alter gene expression. Both integrin activity and the actin cytoskeleton are carefully regulated, and mutations in genes encoding for integrin and actin regulators associate with plethora of diseases. However, less is known if integrin-based adhesions and the actin cytoskeleton are regulated by the same factors.

In this thesis, I have investigated the role of two known integrin inhibitors, SHANK3 and SHARPIN, in regulation of the actin cytoskeleton, and whether this occurs synergistically with regulation of integrins and cell adhesion. I have characterised novel interaction partners for both SHANK3 and SHARPIN, and defined their functions in regulating the cellular actin cytoskeleton, cell adhesion and cell migration. Furthermore, I have investigated how SHARPIN regulates integrin activity at tissue level and find that integrin inhibition can ameliorate the effects of SHARPIN loss in vivo. Importantly, the findings presented in my thesis provide novel insights that can be used to understand pathogenesis of cancer, neuropsychiathric disorders and psoriasis-like dermatitis.