Requirement of Nck adaptors for actin dynamics and cell migration stimulated by platelet-derived growth factor B

Rivera, Gonzalo; Antoku, Susumu; Gelkop, Sigal; Shin, Nah-Young; Hanks, Steven K.; Pawson, Tony; Mayer, Bruce J.

doi:10.1073/pnas.0603786103

Cited by 71 publications

(89 citation statements)

References 30 publications

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“…Dorsal ruffles are thought to constitute a non-clathrin pathway for the sequestration and internalization of tyrosine kinase receptors (26). A similar correlation between Nck and the formation of dorsal ruffles has been observed in another study (27). Interestingly, dorsal ruffles are also missing in cells lacking N-WASP or WAVE1 (28,29).…”

Section: Discussionsupporting

confidence: 56%

“…Observations of PI3K-independent PDGF-induced chemotaxis also suggest that Nck is involved this process (33). Nck is also likely to collaborate with the Crk-associated substrate (p130 Cas ) during PDGF-BB-induced cell migration (27). We noticed that the PDGF-BB-induced chemotactic capacity of the KO cells was reduced to half that of the maximum capacity seen in wild-type cells.…”

Section: Discussionmentioning

confidence: 60%

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Nck Adapters Are Involved in the Formation of Dorsal Ruffles, Cell Migration, and Rho Signaling Downstream of the Platelet-derived Growth Factor β Receptor

Ruusala

Pawson

Heldin

et al. 2008

Journal of Biological Chemistry

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The SH3 and SH2 domain-containing adapter proteins Nck1 and Nck2 are known to function downstream of activated tyrosine kinase receptors, such as the platelet-derived growth factor (PDGF) receptors. The SH2 domain of Nck1 binds to phosphorylated tyrosine residue 751 in PDGF␤ receptor and has been suggested to have a role in the PDGF-induced mobilization of the actin filament system. Because Tyr-751 is a site for additional receptor interactors, it has been difficult to discriminate the signaling from Nck from signaling via other molecules. For this reason we have used mouse embryonic fibroblasts derived from mice in which the genes for Nck1 and Nck2 have been inactivated by gene targeting (knock-out (KO) cells). The mutant cells had a reduced ability to form edge ruffles in response to PDGF, and the presence of Nck was obligatory for the formation of dorsal ruffles. In addition, the KO cells had a reduced chemotactic and migratory potential. Importantly, KO cells had reduced cell attachment properties and a reduced ability to form focal adhesions in response to serum stimulation. Moreover, signaling involving the Rho GTPases was defective in KO cells. In summary, our observations suggest that the Nck adapters are needed for signaling to Rho GTPases and actin dynamics downstream of the PDGF␤ receptor.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 60%

Nck Adapters Are Involved in the Formation of Dorsal Ruffles, Cell Migration, and Rho Signaling Downstream of the Platelet-derived Growth Factor β Receptor

Ruusala

Pawson

Heldin

et al. 2008

Journal of Biological Chemistry

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“…Mouse embryonic fibroblast (MEF) cell lines generated from Nck1+/ +;Nck2+/+ (Nck1+/Nck2+), Nck12/2;Nck2+/+ (Nck12/ Nck2+), Nck1+/+;Nck22/2 (Nck1+/Nck22) and Nck12/ 2;Nck22/2 (Nck12/Nck22) embryos were kindly provided by Tony Pawson (Samuel Lunenfeld Research Institute, Toronto, ON, Canada) and have been described previously (Bladt et al, 2003;Gruenheid et al, 2001). Nck12/Nck22 cells complemented with wild-type human Nck1 or a dominant-negative version of Nck1 with inactivating mutations in all three SH3 domains (Kall) were kindly provided by Tony Pawson (Samuel Lunenfeld Research Institute) and have been described previously (Rivera et al, 2006;Tanaka et al, 1995). Cell lines were grown in Dulbecco's minimal Eagle's medium (DMEM) supplemented with 10 % (v/v) fetal calf serum (DMEM/ FCS) at 37 uC in a humidified atmosphere with 5 % CO 2 .…”

Section: Methodsmentioning

confidence: 99%

Src homology domain 2 adaptors affect adherence of Salmonella enterica serovar Typhimurium to non-phagocytic cells

et al. 2007

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The ability of Salmonella enterica serovar Typhimurium (S. Typhimurium) to penetrate the intestinal epithelium is key to its pathogenesis. Bacterial invasion can be seen as a two-step process initially requiring adherence to the host cell surface followed by internalization into the host cell. Evidence suggests that adherence of S. Typhimurium to host cells is receptor-mediated; however, the host cell receptor(s) has/have not been identified. Internalization of S. Typhimurium absolutely requires the actin cytoskeleton yet only a few of the cytoskeletal components involved in this process have been identified. In order to identify host proteins that may play a role in S. Typhimurium invasion, the recruitment of actin-associated proteins was investigated. The contribution of recruited Src homology 2 adaptor proteins to invasion was further investigated and it was found that, while not involved in bacterial internalization itself, the adaptors Nck and ShcA influenced adherence of S. Typhimurium to non-phagocytic cells.

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“…Therefore, the authors of this study concluded that Nck␣ and Nck␤ are functionally redundant during mouse development. However, an increasing number of studies have also provided evidence that Nck␣ and Nck␤ have rather nonoverlapping functions in various type of cells (5,6,14,19,21,25). So far, no Nck␣-or Nck␤-specific downstream target proteins have been identified, and it has obviously become critical to further understand the underlying mechanisms.…”

mentioning

confidence: 99%

Nckβ Adapter Controls Neuritogenesis by Maintaining the Cellular Paxillin Level

Guan

Chen

Woodley

et al. 2007

Molecular and Cellular Biology

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The SH2/SH3 adapter Nck has an evolutionarily conserved role in neurons, linking the cell surface signals to actin cytoskeleton-mediated responses. The mechanism, however, remains poorly understood. We have investigated the role of Nck/Nck␣/Nck1 versus Grb4/Nck␤/Nck2 side-by-side in the process of mammalian neuritogenesis. Here we show that permanent genetic silencing of Nck␤, but not Nck␣, completely blocked nerve growth factor-induced neurite outgrowth in PC12 cells and dramatically disrupted the axon and dendrite tree in primary rat cortical neurons. By screening for changes among the components reportedly present in complex with Nck, we found that the steady-state level of paxillin was significantly reduced in Nck␤ knockdown, but not Nck␣ knockdown, neurons. Interestingly, Nck␤ knockdown did not affect the paxillin level in glial cells and several other cell types of various tissue origins. Genetic silencing of paxillin blocked neuritogenesis, just like Nck␤ knockdown. Reintroducing a nondegradable Nck␤ into Nck␤ short interfering RNA-expressing PC12 cells rescued paxillin from down-regulation and allowed the resumption of neuritogenesis. Forced expression of paxillin in Nck␤ knockdown PC12 also rescued its capacity for neuritogenesis. Finally, Nck␤, but not Nck␣, binds strongly to paxillin and treatment of the neurons with proteosome inhibitors prevented paxillin down-regulation in Nck␤ knockdown neurons. Thus, Nck␤ maintains paxillin stability during neuritogenesis.

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Requirement of Nck adaptors for actin dynamics and cell migration stimulated by platelet-derived growth factor B

Abstract: Crk-associated substrate ͉ actin cytoskeleton ͉ SH2 domain ͉ SH3 domain ͉ tyrosine phosphorylation

Cited by 71 publications

References 30 publications

Nck Adapters Are Involved in the Formation of Dorsal Ruffles, Cell Migration, and Rho Signaling Downstream of the Platelet-derived Growth Factor β Receptor

Nck Adapters Are Involved in the Formation of Dorsal Ruffles, Cell Migration, and Rho Signaling Downstream of the Platelet-derived Growth Factor β Receptor

Src homology domain 2 adaptors affect adherence of Salmonella enterica serovar Typhimurium to non-phagocytic cells

Nckβ Adapter Controls Neuritogenesis by Maintaining the Cellular Paxillin Level

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