Cortactin has been shown in vitro to bind and activate N WASP through an SH3 proline wealthy 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 boost the proteins binding to and activation of N WASP. Conversely, Src phosphoryla tion inhibits the capability of both Erk phosphorylated cort actin, and that doubly mutated S405,418D cortactin, to activate N WASP. In addition, phospho mimetic muta tion with the 3 tyrosine residues targeted by Src inhibited the capability of S405,418D cort actin to activate N WASP.
These final results led us to hypothe size that Erk phosphorylation liberates the SH3 domain of cortactin from intramolecular interactions, enabling it to synergize with N WASP in activating the Arp2 3 complicated, and that Src phosphorylation terminates cortactin activa discover more here 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 possibly be relevant for actin dynamics in several cell processes and it might partially explain the coordinated action of cortactin and N WASP proteins, therefore connecting the two major families of Arp2 three complicated activators. Constant with this model, current 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 many cell systems.
For example, serine phosphorylation of cortactin has been proposed to be relevant for actin polymerization, even though tyrosine phosphorylation have already been shown to selectively handle adhesion turnover. This suggests that distinct phosphocortactin forms par ticipate in distinct signaling pifithrin a pathways. Although it really is clear that cortactin participates in pedestal actin dynamics, the underlying mechanism is not well understood. Prior research have shown that cortactin translocates to EPEC pedestals. More than expression of trun cated forms of cortactin blocks pedestal formation. A comply with up study to this perform focused on the function of cortac tin domains and Erk Src phosphorylation, and it con firmed that truncated types of cortactin exert a dominant negative impact in pedestal formation by EPEC and EHEC.
This study suggests that cortactin is recruited through its helical area, plus the authors conclude that tyrosine phosphorylation is rel evant to pedestal formation, whereas serine phosphoryla tion seems to possess no effect on actin assembly underneath the bacteria. However, this conclusion is based exclu sively on experiments with phosphorylation mimicking mutants, without having any comparison together with the corresponding non phosphorylatable counterparts.