Integrin activation signaling mechanisms triggered by arrest chemokines (Frontiers topic)

Signaling network involved in integrin activation by chemokines

The rho- rap-macro module of integrin affinity regulation
RED nodes = pro-adhesive role ; BLUE nodes = anti-adhesive role

Figure 6
The expanded rho- rap-macro module of integrin affinity regulation

Model of concurrent involvement of VAV1, SOS1, DOCK2, and ARHGEF1 GEFs in JAKs and Gαi-dependent rho module activation controlling LFA-1 affinity triggering by chemokines. CXCR4 engagement by CXCL12 induces LFA-1 affinity triggering through the concurrent upstream activity of JAK PTKs and heterotrimeric Gαi protein leading to activation of multiple rho-GEFs. Whereas VAV1 activation is dependent only on JAK kinase activity, SOS1, DOCK2, and ARHGEF1 are equivalently controlled by Gαi protein and JAKs. In turn, VAV1, SOS1, ARHGEF1, and DOCK2 cooperate to activate RhoA and Rac1. Additionally, Rap1A activation is dependent on both JAK-activated RhoA and PLC regulation by heterotrimeric Gαi protein. Together, the Rho and Rap modules coordinately regulate the activity of several actin/integrin-binding proteins (FERMT3, Kindlin3; TLN1, Talin1; CYTH1, Cytohesin-1; RIAM and RASSF5, RAPL), thus leading to the regulation of LFA-1–mediated rapid arrest.

The updated rho_rap-module of integrin regulation 2018

The expanded rho- rap-macro module of integrin affinity regulation 2018

In B-lymphocytes, BTK is a downstream effector of JAK PTKs, concurrently with heterotrimeric Gαi protein, to lead to the full activation of the rho-rap module of integrin affinity triggering (see CXCR4- and BCR-triggered integrin activation in B-cell chronic lymphocytic leukemia cells depends on JAK2-activated Bruton's tyrosine kinase, Oncotarget. 2018; 9:35123-35140.

From Front Immunol. 2012;3:127

See also the updated list (31/03/2021) of all signalling proteins involved in the
regulation of rapid integrin activation and mediated adhesion (HGNC protein IDs).
Listed are both protein positively or negatively regulating integrin activation state.

Note that not all listed proteins respect thefour criteriafor integrin affinity triggering described
Front Immunol. 2012;3:127.