Cortactin has been shown in vitro to bind and activate N WASP by way of an SH3 proline rich domain interaction. This activation is regulated pos itively and negatively when cortactin is phosphorylated by Erk and Src respectively. Erk phosphorylation of cortactin or the double mutation S405,418D in cortactin that mim ics this phosphorylation enhance the proteins binding to and activation of N WASP. Conversely, Src phosphoryla tion inhibits the potential of each Erk phosphorylated cort actin, and that doubly mutated S405,418D cortactin, to activate N WASP. In addition, phospho mimetic muta tion in the 3 tyrosine residues targeted by Src inhibited the capacity of S405,418D cort actin to activate N WASP.
These results led us to hypothe size that Erk phosphorylation liberates the SH3 domain of cortactin from intramolecular interactions, permitting it to synergize with N WASP in activating the Arp2 3 complex, and that Src phosphorylation terminates cortactin activa selleck inhibitor tion of N WASP. This proposed on off switching mecha nism suggests that phosphorylation of cortactin regulates the accessibility and or affinity of its SH3 domain towards its targets. S Y model may be relevant for actin dynamics in numerous cell processes and it may partially clarify the coordinated action of cortactin and N WASP proteins, therefore connecting the two major families of Arp2 3 complex activators. Constant with this model, recent structural information showed that cortactin adopts a closed globular conformation in which its SH3 domain interacts together with the actin binding repeats. This model has opened up new directions for studies in numerous cell systems.
For example, serine phosphorylation of cortactin has been proposed to become relevant for actin polymerization, when tyrosine phosphorylation have already been shown to selectively handle adhesion turnover. This suggests that distinctive phosphocortactin types par ticipate in distinct signaling inhibitor MK-2206 pathways. Though it truly is clear that cortactin participates in pedestal actin dynamics, the underlying mechanism is not nicely understood. Prior research have shown that cortactin translocates to EPEC pedestals. More than expression of trun cated types of cortactin blocks pedestal formation. A stick to up study to this work focused on the role of cortac tin domains and Erk Src phosphorylation, and it con firmed that truncated forms of cortactin exert a dominant damaging impact in pedestal formation by EPEC and EHEC.
This study suggests that cortactin is recruited through its helical area, along with the authors conclude that tyrosine phosphorylation is rel evant to pedestal formation, whereas serine phosphoryla tion seems to have no impact on actin assembly underneath the bacteria. Having said that, this conclusion is primarily based exclu sively on experiments with phosphorylation mimicking mutants, without having any comparison together with the corresponding non phosphorylatable counterparts.