MIME-Version: 1.0 Content-Type: multipart/related; boundary="----=_NextPart_01C5DED6.4D591AE0" This document is a Single File Web Page, also known as a Web Archive file. If you are seeing this message, your browser or editor doesn't support Web Archive files. Please download a browser that supports Web Archive, such as Microsoft Internet Explorer. ------=_NextPart_01C5DED6.4D591AE0 Content-Location: file:///C:/99125913/MyosinHeavyChainKinases.htm Content-Transfer-Encoding: quoted-printable Content-Type: text/html; charset="us-ascii" Dictyostelium Myosin Heavy Chain Kinases

Dictyostelium Myosin Heavy Chain Kinases

 

 

Myosin II filament assembly in= Dictyostelium is regulated via Myo= sin heavy chain (MHC) phosphorylation through the combined activities of at lea= st one MHC phosphatase and a group of MHC kinases (De la Roche et al., 2002; Yumura et al., 2005).  Myosin Heavy Chain Kinase A was the first of the heavy chain kinases to be identifi= ed and purified, and cellular and biochemical studies of MHCK A demonstrated that = the activity of this kinase drives myosin filament disassembly both in vitro and in vivo by phosphorylating the regu= latory threonine sites of MHC (Cote and Bukiejko, 1987).  Cloning and sequence analysis of t= he MHCK A gene revealed a novel, modular organization to the protein (Figure 3) (Futey et al., 1995).  The amino-terminal domain of MHCK = A is predicted to have significant a-helical coiled-coil structure and has been shown biochemically to mediate MHCK A oligomerization (Kolman and Egelhoff, 1997).  The central catalytic region of MH= CK A is the prototype for a novel family of protein kinases= , referred to as &q= uot;a-kinases&q= uot;, which do not exhibit any apparent sequence similarity to any of the conventional protein kinase families (Drennan<= /span> and Ryazanov, 2004; Egelho= ff, 1999; Futey et al., 1995).  Representatives of this kinase fam= ily have been identified in diverse groups of organisms including several kinases in Di= ctyostelium (Yumura et al., 2005), as well as others in mammali= an systems that include eukaryotic elongation factor-2 ki= nases and the Channel-kinase TRPM7/ChaK1 (Drennan<= /span> and Ryazanov, 2004).  At its carboxyl-terminus, MHCK A possesses a domain containing a 7-fold WD repeat motif (Sondek and Siderovski, 2001) that facilitates phosphorylat= ion of myosin heavy chain by physically targeting MHCK A directly to myosin II filaments (Steimle et al., 2001a)= .

 

 Localization studies in chemotaxing cells revealed that MHCK A is recruited to sites of pseudopod formation at the cell anteri= or (Figure 5) (Steimle et al., 2001b)= .  In the context of cytokinesis, MHC= K A is enriched at the actin-rich polar regions of the dividing cell (Liang et al., 2002; Nagasaki et al., 2002).  The accumulation of MHCK A at acti= n-rich cell extensions, coupled with reduced levels of myosin II at such sites (De la Roche et al., 2002; Wessels et al., 1988), suggests a model in which my= osin II filament disassembly is promoted at sites of MHCK A enrichment, and thus= myosin II-based cross-linking of actin filaments at regions forming cellular extensions may be relaxed. In turn, this may promote the assembly and reorganization of the actin cytoskeleton necessary for the formation of pseudopodial structures (Heid et al., 2004; Laevsky and Kne= cht, 2003; Steimle et al., 2001b; Stites et al., 199= 8). 

 

 

Analyses of the Dictyostelium genome data base have revealed that there are at least 6 members of the alpha-kinase family in Dictyosteliu= m (Kreppel<= /span> et al., 2004).  Recent studies by Yumura and colleagues indicate that of the Dictyostelium alpha kinases, only three - MHCK A, MHCK B (Rico and Egelhoff, 2003), and MHCK C (Liang et al., 2002; Nagasaki et al., 2002) - appear to have physiologica= lly significant functions in regulating myosin II filament disassembly in the c= ell (Yumura et al., 2005).  Upon initial examination, MHCK A, = B, and C appear to represent functionally redundant activities since they share a common ability to specifically phosphorylate the regulatory threonine residues in the tail of the myosin II heavy chain and drive the disassembly of myosin II bipolar filaments both in vitro and in the cell (Figure 4).

 

The functional differences amo= ng the MHCKs are reflected, in part, by their distinct localization patterns during dynamic cellular processes such as cell migrat= ion and cytokinesis (Figure 5).  I= n a migrating cell, for example, MHCK A is preferentially enriched at sites of pseudopod formation at the cell anterior where the ki= nase is expected to catalyze the disassembly of myosin II-based cross-linking of actin filaments which, in turn, may facilitate the reorganization of the ac= tin cytoskeleton necessary for the formation of cellular extensions (Steimle et al., 2001b)= . 

 

In contrast, MHCK C co-localizes with myosin II at the trailing edge of migrating cells, suggesting a role for this enzyme in = the coordinated turnover of myosin II filaments that mediate contraction of the= cell rear (Liang et al., 2002; Nagasaki et al., 2002).  During cytokinesis, MHCK C exhibits robust localization to the cleavage furrow.  In contrast, MHCK A displays a per= sistent localization at the poles of the dividing cell and at the “anterior&#= 8221; of the migrating daughter cells (Liang et al., 2002; Nagasaki et al., 2002).  Recent studies indicate that MHCK = B, like MHCK C, is recruited to the cleavage furrow during cytokinesis = (Yumura et al., 2005).  It is particularly interesting tha= t MHCK B and MHCK C localizations depend on the presence of myosin II in the cell = (Nagasaki et al., 2002; Yumura et al., 2005); this contrasts with MHCK A localization which does not require myosin II but does depend on the presen= ce of filamentous actin in the cell (Steimle et al., 2001b)= .  Taken together, these results sugg= est that while the three kinases share similar cata= lytic activities, they appear to have distinct functions in regulating myosin II filament assembly in different cellular contexts. 

 

 

 

References

 

Cote, G.P., and U. Bukiejko. 1987. Purification and characterization of a m= yosin heavy chain kinase from Dictyostelium discoideum. J Biol Chem. 262:1065-72.

De la Roche, M.A., J.L. Smith, V. Betapudi, T.T. Egelhoff, and G.P. Cote. 2002. Signaling pathways regulating Dictyostel= ium myosin II. J Mu= scle Res Cell Motil. 23:703-18.

Drennan, D., and A.G. Ryazanov. 2004. Alpha-kinases: analysis of the family and comparison with conventional protein kinases. Prog Biophys Mol Biol. 85:1-32.

Egelhoff, T.T., and = Cote, G.P. 1999. Guidebook t the Cytoskeletal= and Motor Proteins. Oxford University Press, Oxford. 460 - 464 pp.

Futey<= span style=3D'font-family:Arial'>, L.M., Q.G. Medley, G.P. Cote, and T.T. Egelhoff. 1995. Structural analysis of myosin heavy chain kinase A from Dictyostelium= . Evidence for a highly divergent protein kinase domain, an ami= no- terminal coiled-coil domain, and a domain homologous to the beta- subunit o= f heterotrimeric G proteins. J Biol Chem. 270:523-9.<= /span>

Heid, P.J., D. Wessels, K.J. Daniels, D.P. Gibson, H. Zhang, E. Voss= , and D.R. Soll. 2004. The role of myosin heavy chain phosphorylation in Dictyostelium motility, chemotaxis and F-actin localizat= ion. J Cell Sci. 117:4819-35.

Kolman= , M.F., and T.T. Egelhoff<= /span>. 1997. Dictyostelium myosin heavy chain kinase = A subdomains. Coiled-coil = and wd repeat roles in oligomerization and substrate targe= ting. J Biol Che= m. 272:16904-10.

Kreppel, L., P. Fey,= P. Gaudet, E. Just, W.A. Kibbe, R.L. Chisholm, and A.R. Kimmel. 2004. dictyBase: a new Dictyostelium discoideum genome database. Nucleic Acids Res. 32:D332-3.

Laevsky, G., and D.A. Knecht. 2003. Cross-linking of actin filaments by myos= in II is a major contributor to cortical integrity and cell motility in restricti= ve environments. J Cell Sci. 116:3761-70.

Liang<= span style=3D'font-family:Arial'>, W., L. Licate, H. Warrick, J. Spudich, and T. Egelhoff. 2002. Differential localization in cells of myosin II heavy chain <= span class=3DSpellE>kinases during cytokinesis and polarized migration. BMC Cell Biol. 3:19.

Murphy, M.B., and T.T. Egelhoff.<= /span> 1999. Biochemical characterization of a Dictyostelium myosin II heavy-chain phosphatase= that promotes filament assembly. Eur J Biochem. 264:582-90.

Murphy, M.B., S.K. Levi, and T.T. Egelhoff. 1999. Molecular characterization and immunolocalization of Dictyostelium discoideum protein phosphatase 2A. FEBS Lett. 456:7-12.

Nagasaki, A., G. Itoh, S. Yumura, and T.Q. Uyeda. 2002. Novel Myosin Heavy Chain Kinase Involved in Disassembly of My= osin II Filaments and Efficient Cleavage in Mitotic Dictyostelium Cells. Mol Biol Cell. 13:4333-42.

Rico, M., and T.T. Egelhoff. 2003. Myosin heavy chain kinase B participates= in the regulation of myosin assembly into the cytoskeleton. J Cell Biochem. 88:521-32.

Sondek= , J., and D.P. Siderovski<= /span>. 2001. Ggamma-like = (GGL) domains: new frontiers in G-protein signaling and beta-propeller scaffoldin= g. Biochem Pharmacol= . 61:1329-37.

Steimle, P.A., T. Naismith, L. Licate, and T.T. Egelhoff. 2001a. WD repeat domains target dictyostelium myosin heavy chain kinases by binding directly = to myosin filaments. J Biol Chem. 276:6853-60.

Steim= le, P.A., S. Yumura, G.P. Cote, Q.G. Medley, M.V. <= span class=3DSpellE>Polyakov, B. Leppert, and= T.T. Egelhoff. 2001b. Recruitment of a= myosin heavy chain kinase to actin-rich protrusions in Dictyostelium. Curr Biol. 11:708-13.

Stites= , J., D. Wessels, A= . Uhl, T. Egelhoff, D. Shutt, and D.R. Soll. 1998. Phosphorylation of the Dictyostelium myo= sin II heavy chain is necessary for maintaining cellular polarity and suppressing turning during chemotaxis. Cell Motil Cytoskeleton. 39:31-51.

Wessels, D., D.R. Soll, D.= Knecht, W.F. Loomis, A. De Lozan= ne, and J. Spudich. 1988. Cell motility and chemotaxis in Dictyostelium amebae lacking myosin heavy chain. Dev Bio= l. 128:164-77.

Yumura, S., M. Yoshi= da, V. Betapudi, L.S. Licate, Y. = Iwadate, A. Nagasaki, T.Q. Uyeda, and T.T. Egelhoff. 2005. Multiple Myosin II Heavy Chain Kinases: R= oles in Filament Assembly Control and Proper Cytokinesis in Dictyostelium. Mol Biol Cell.

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