Myosin IIA drives neurite retraction - PubMed (original) (raw)

Figure 7.

Scheme to illustrate the separate functions and regulation of conventional nonsarcomeric myosin IIA and myosin IIB. We propose separate pathways to regulate the distinctive functions of nonsarcomeric, conventional myosin isoforms, in particular with regard to the dynamic process of neurite extension. We have shown (this study) that myosin IIA is the motor involved in neurite retraction, a process that can be triggered by a number of effectors, including LPA (Tigyi and Miledi, 1992; Jalink et al., 1993, 1994; Tigyi et al., 1996b) and thrombin (Jalink and Moolenaar, 1992; Suidan et al., 1992; Jalink et al., 1994). A direct pathway relating cause and effect is shown (LHS) and involves Rho activation, which, in turn, activates Rho-kinase (Matsui et al., 1996; Ridley, 1996; Bishop and Hall, 2000). When the myosin binding subunit (MBS) of myosin light chain phosphatase (MLCP) is phosphorylated by activated Rho-kinase (Kimura et al., 1996; Ridley, 1996), dephosphorylation of the regulatory light chain (RLC) of myosin is inhibited, allowing myosin IIA to maintain a level of activity determined by the level of phosphorylation at Ser19 on the RLC (Bresnick, 1999). The activity of Rho-kinase is inhibited by Y27632 (Uehata et al., 1997; Davies et al., 2000), leading to activation of MLCP, dephosphorylation of myosin IIA and a decline in cross-bridge cycling, preventing retraction. Interestingly, in vitro studies have demonstrated that the heavy chain of myosin IIA can act as a substrate for protein kinase C (Murakami et al., 1995) and metastasis-associated protein (Mts 1) (Murakami et al., 2000) so dual, or even triple, regulation at the level of the myosin molecule may also be possible. Myosin IIA is also known to be involved in focal contact and stress fiber formation (Chrzanowska-Wodnicka and Burridge, 1996; Wei and Adelstein, 2000; Wylie and Chantler, 2001), processes that can be also be inhibited by Y27632 (Uehata et al., 1997). It is likely that there are other intermediates in the pathway shown as indicated by a requirement for two different tyrosine kinases (Aoki et al., 1999). We have shown previously that myosin IIB is involved in neurite outgrowth (Wylie et al., 1998), a process that can be initiated in many neuronal cells by nerve growth factor (Gundersen, 1985) or bradykinin (van Leeuwen et al., 1999) (although not required to stimulate outgrowth in the case of Neuro-2A cells). A proposed chain of command is shown (RHS) in which agonist binding activates Rac, leading ultimately to activation of a myosin heavy chain kinase (MHCK) (van Leeuwen et al., 1999). Phosphorylation of the myosin heavy chain has been shown to correlate with cell spreading (van Leeuwen et al., 1999). We propose that myosin IIB is also activated by MHCK in Neuro-2A cells, leading to neurite outgrowth. Casein kinase II and protein kinase C have been implicated as possible candidates for MHCK by in vitro experiments (Murakami et al., 1998). PAK-kinase may also be involved (Sanders et al., 1999; van Leeuwen et al., 1999) and has been demonstrated to phosphorylate the RLC (Chew et al., 1998) in vitro. Once again, the results suggest that some form of dual regulation at the level of the myosin molecule may occur. Putative cross talk between the pathways has not been included in the interest of clarity but may involve reciprocal actions of cAMP (Hirose et al., 1998), PAK (van Leeuwen et al., 1999), and further actions of the small GTPase protein family (Ridley, 1996; Sander et al., 1999; Bishop and Hall, 2000; Yuan et al., 2003).