Nck and Phosphatidylinositol 4,5-Bisphosphate Synergistically Activate Actin Polymerization through the N-WASP-Arp2/3 Pathway

Rohatgi, Rajat; Nollau, Peter; Ho, Hsin‐Yi Henry; Kirschner, Marc W.; Mayer, Bruce J.

doi:10.1074/jbc.m103856200

Cited by 369 publications

(323 citation statements)

References 26 publications

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“…2C), which is predicted to be in closed conformation, suggest that NIK might bind ERM proteins. An in vitro binding assay confirmed that in vitro-translated 35 S-labeled NIK bound a GST fusion of the N terminus of moesin (M1-310) but not the C terminus (M287-577) or GST (Fig. 6A).…”

Section: Nik Binds the N Terminus Of Moesinmentioning

confidence: 80%

“…Our finding that NIK activity is necessary to phosphorylate ERM proteins in response to EGF and PDGF, but not to thrombin, is consistent with NIK binding to the Src homology 3 domain of Nck (1), an adaptor protein associated with receptor tyrosine kinases, and with Msn binding to DOCK (10), the Drosophila ortholog of Nck. Nck also binds and activates the Wiskott-Aldrich syndrome protein WASP (35) and the WASP family verprolin homologous protein WAVE (36), which promote actin assembly by the Arp2͞3 complex and membrane protrusion. Although NIK may act coordinately with Nck to regulate membrane dynamics, its phosphorylation of ERM proteins can occur independently of Nck because truncated NIK 1-321 lacking the C-terminal Nck-binding domain was sufficient to increase phosphorylation of ERM proteins in quiescent cells.…”

Section: Discussionmentioning

confidence: 99%

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The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors

Baumgärtner

Sillman²,

Blackwood³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

124

150

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The mammalian Ste20-like Nck-interacting kinase (NIK) and its orthologs Misshapen in Drosophila and Mig-15 in Caenorhabditis elegans have a conserved function in regulating cell morphology, although through poorly understood mechanisms. We report two previously unrecognized actions of NIK: regulation of lamellipodium formation by growth factors and phosphorylation of the ERM proteins ezrin, radixin, and moesin. ERM proteins regulate cell morphology and plasma membrane dynamics by reversibly anchoring actin filaments to integral plasma membrane proteins. In vitro assays show that NIK interacts directly with ERM proteins, binding their N termini and phosphorylating a conserved C-terminal threonine. In cells, NIK and phosphorylated ERM proteins localize at the distal margins of lamellipodia, and NIK activity is necessary for phosphorylation of ERM proteins induced by EGF and PDGF, but not by thrombin. Lamellipodium extension in response to growth factors is inhibited in cells expressing a kinase-inactive NIK, suppressed for NIK expression with siRNA oligonucleotides, or expressing ezrin T567A that cannot be phosphorylated. These data suggest that direct phosphorylation of ERM proteins by NIK constitutes a signaling mechanism controlling growth factor-induced membrane protrusion and cell morphology.ezrin ͉ moesin ͉ ste20 kinase ͉ membrane protrusion T he Nck-interacting kinase (NIK) is a member of the germinal center kinase subfamily of Ste20͞MAP4K serine͞threonine kinases (1). Closely related to NIK are the mammalian kinases TNIK (2), MINK (3), and NRK͞NESK (4) and orthologs Misshapen (Msn) in Drosophila (5) and MIG-15 in Caenorhabditis elegans (6). NIK and its orthologs share a common function in regulating cell shape and migration. In mice, homozygous knockout of NIK results in early embryonic lethality with defects in mesoderm migration (7), and expression of kinase-inactive NIK attenuates epithelial cell invasion (8). Msn functions in determining epithelial polarity, dorsal closure. and neuronal targeting (5, 9, 10), and MIG-15 controls axonal navigation (6). NIK (1) and Msn (5) also share a conserved activation of the JNK pathway. NIK, however, does not directly phosphorylate JNK, nor do NIK nullizygous embryos precisely phenocopy mice lacking JNK1 or JNK2 (7). Additionally, activation of JNK is not associated with dynamic changes in cell morphology. Hence, NIK substrates that control cell morphogenesis have not been identified.We now report that the ERM proteins ezrin, radixin, and moesin are substrates for NIK. ERM proteins regulate cell morphology by cross-linking actin filaments to the plasma membrane. The N-terminal FERM (4.1 ERM) domain of ERM proteins binds to integral plasma membrane proteins and the C terminus binds F-actin (11). ERM proteins control cell shape primarily by regulating membrane protrusions and cell-substrate adhesion. In epithelial cells ERM proteins are necessary for the formation of apical microvilli (12)(13)(14). In fibroblasts ERM proteins regulate the assembly of focal adhesions (...

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Section: Nik Binds the N Terminus Of Moesinmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors

Baumgärtner

Sillman²,

Blackwood³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

124

150

View full text Add to dashboard Cite

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“…More backwards, but still at the front Rac1 GTPase regulates actin polymerization, which forms a mesh-like network controlling lamellipodia extension and formation of nascent cell-substratum adhesion. Rac1 directly activate the WAVE family of actin nucleators and phosphoinositides, which are required for activity of actin-nucleating proteins including N-WASP-Arp2/3 complex (Burridge and Wennerberg, 2004;Rohatgi et al, 2001). Finally, at the rear RhoA small GTPase promotes assembly of stress fibers and mature focal adhesions (Burridge and Wennerberg, 2004;.…”

Section: Establishment Of Cell Polaritymentioning

confidence: 99%

Controlled levels of canonical Wnt signaling are required for neural crest migration

Maj

Künneke

Loresch

et al. 2016

Developmental Biology

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“…Nck binds phosphorylated SLP-76 (Wunderlich et al 1999) and WASp (Wiskott-Aldrich syndrome protein) (Rohatgi et al 2001;BardaSaad et al 2005), bringing WASp in proximity to Vav. Vav recruits and activates Cdc42, which is necessary for WASp activation.…”

Section: Molecules Recruited To Lat Via Slp-76 Promote T-cell Activationmentioning

confidence: 99%

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

Balagopalan¹,

Coussens²,

Sherman³

et al. 2010

Cold Spring Harbor Perspectives in Biology

150

184

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The adapter molecule LAT is a nucleating site for multiprotein signaling complexes that are vital for the function and differentiation of T cells. Extensive investigation of LAT in multiple experimental systems has led to an integrated understanding of the formation, composition, regulation, dynamic movement, and function of LAT-nucleated signaling complexes. This review discusses interactions of signaling molecules that bind directly or indirectly to LAT and the role of cooperativity in stabilizing LAT-nucleated signaling complexes. In addition, it focuses on how imaging studies visualize signaling assemblies as signaling clusters and demonstrate their dynamic nature and cellular fate. Finally, this review explores the function of LAT based on the interpretation of mouse models using various LAT mutants.

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Nck and Phosphatidylinositol 4,5-Bisphosphate Synergistically Activate Actin Polymerization through the N-WASP-Arp2/3 Pathway

Cited by 369 publications

References 26 publications

The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors

The Nck-interacting kinase phosphorylates ERM proteins for formation of lamellipodium by growth factors

Controlled levels of canonical Wnt signaling are required for neural crest migration

The LAT Story: A Tale of Cooperativity, Coordination, and Choreography

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