Montresor et al. describe how the JAK family of tyrosine kinases promotes leukocyte adhesion.

A key step in the recruitment of leukocytes to sites of damage or infection is the activation of integrin adhesion molecules by chemokines so that the cells can attach to blood vessel walls and exit the blood stream. The chemokine CXCL12, for example, shifts the T cell integrin LFA-1 to a high-affinity conformation by activating the GTPases RhoA and Rac1 and their downstream effectors phospholipase D1 (PLD1) and PIP5K1C. But how CXCL12 activates this Rho signaling module is unclear.

Janus kinases (JAKs) can activate signaling pathways downstream of chemokine receptors, and Montresor et al. found that JAK2 and JAK3 were activated in T cells treated with CXCL12. Knocking down or inhibiting these JAKs suppressed the activation of LFA-1 by CXCL12, reducing T cell adhesion in vitro and in vivo. JAKs activated the Rho signaling module by phosphorylating the guanine nucleotide exchange factor VAV1, the researchers found.

JAK signaling was also required for the activation of a second signaling module, involving the small GTPase Rap1, that has been independently implicated in chemokine-induced integrin activation. Surprisingly, Rap1 activation depended on RhoA and PLD1, indicating that Rap1 acts downstream of the Rho signaling module. Senior author Carlo Laudanna now wants to determine the mechanism by which RhoA and PLD1 control Rap1’s activation and to investigate how these signaling pathways differ in other blood cells and in leukemias.

References

References
Montresor
A.
et al
.
2013
.
J. Cell Biol.
.

Author notes

Text by Ben Short