Functional characterization of Rho GTPase activating proteins SYDE1 and SYDE2

The human genome contains over 60 proteins with Rho GTPase activating protein (RhoGAP) domains, many of which are not yet well understood in terms of their target specificity and biological functions. SYDE1 and SYDE2 are two such orphan RhoGAPs that lack substantial research on their biochemical and cellular functions, with some conflicting evidence pointing towards their specific GTPases. Previously, researchers identified SYDE1 and SYDE2 through a screen searching for substrates of c-Jun N-terminal kinases (JNKs).

In this study, the authors discovered that SYDE1 and SYDE2 are largely phosphorylated by JNK1 compared to other mitogen-activated protein kinases (MAPKs) at sites close to a kinase docking region. Further investigations revealed that both purified SYDE1 and SYDE2 exhibit substantial catalytic GAP activity towards RhoA, Rac1, and Cdc42. However, the study also found that altering the expression of SYDE1 and SYDE2 does not produce measurable differences in the overall GTP loading of these GTPases.

Despite this, the research team demonstrates that SYDE1 and SYDE2, in a partially GTPase-dependent manner, promote cell spreading and the formation of more focal adhesions, and enhance directional persistence in cell migration within HEK293 cells. The findings of this study establish SYDE1 and SYDE2 as reliable JNK substrates with catalytic activity towards a group of Rho GTPases. Additionally, the study provides insights into the fundamental roles of SYDE1 and SYDE2 in regulating cell morphology, adhesion, and migration.