ERK5 promotes Src-induced podosome formation by limiting Rho activation

Schramp, Mark; Ying, Olivia; Kim, Tai Young; Martin, G S

doi:10.1083/jcb.200801078

Cited by 47 publications

(43 citation statements)

References 64 publications

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“…English and coworkers suggested that Ras could regulate ERK5 activity (English et al, 1999) and Kamakura and coworkers proposed that Ras was important in EGF activation of ERK5 (Kamakura et al, 1999), in direct contrast to an earlier study investigating EGF activation of ERK5 (Kato et al, 1998). The non-receptor tyrosine kinase, Src, activates ERK5 (Schramp et al, 2008) and Src has been proposed as an intermediate in EGF stimulation of ERK5 activity (Sun et al, 2003). Recent studies investigating ERK5 as a downstream target of brain-derived neurotrophic factor (BDNF) activity (Wang et al, 2006b) have identified a Rap1-MEKK2 signalling cascade that activates ERK5; Ras and MEKK3 did not have a significant role.…”

Section: Discussionmentioning

confidence: 99%

MEK5 and ERK5 are mediators of the pro-myogenic actions of IGF-2

Carter

Cosgrove

Gonzalez

et al. 2009

Journal of Cell Science

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During the differentiation of muscle satellite cells, committed myoblasts respond to specific signalling cues by exiting the cell cycle, migrating, aligning, expressing muscle-specific genes and finally fusing to form multinucleated myotubes. The predominant foetal growth factor, IGF-2, initiates important signals in myogenesis. The aim of this study was to investigate whether ERK5 and its upstream MKK activator, MEK5, were important in the pro-myogenic actions of IGF-2. ERK5 protein levels, specific phosphorylation and kinase activity increased in differentiating C2 myoblasts. ERK5-GFP translocated from the cytoplasm to the nucleus after activation by upstream MEK5, whereas phospho-acceptor site mutated (dominant-negative) ERK5AEF-GFP remained cytoplasmic. Exogenous IGF-2 increased MHC levels, myogenic E box promoter-reporter activity, ERK5 phosphorylation and kinase activity, and rapidly induced nuclear localisation of ERK5. Transfection with antisense Igf2 decreased markers of myogenesis, and reduced ERK5 phosphorylation, kinase and transactivation activity. These negative effects of antisense Igf2 were rescued by constitutively active MEK5, whereas transfection of myoblasts with dominant-negative MEK5 blocked the pro-myogenic action of IGF-2. Our findings suggest that the MEK5-ERK5 pathway is a novel key mediator of IGF-2 action in myoblast differentiation.

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Section: Discussionmentioning

confidence: 99%

MEK5 and ERK5 are mediators of the pro-myogenic actions of IGF-2

Carter

Cosgrove

Gonzalez

et al. 2009

Journal of Cell Science

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“…36,37 In addition, the blockade of RhoA signaling significantly increased podosome formation in myeKlf5 −/− macrophages, suggesting KLF5-independnet podosome formation. Indeed, Mark Schramp et al 38 reported that ERK5 promotes Src-induced podosome formation in Src-transformed fibroblasts by limiting Rho activation. Pathways through which KLF5 modulates Rho activity, podosome formation, and cellular invasion are of considerable interest.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of KLF5–Myo9b–RhoA Pathway–Mediated Podosome Formation in Macrophages Ameliorates Abdominal Aortic Aneurysm

Zheng

Suzuki

et al. 2017

Circulation Research

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A bdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by the remodeling of the aortic wall, and it frequently leads to high morbidity and mortality because of vascular dissection and rupture.1 Although AAA formation is a multifactorial process involving the infiltration of macrophages, release of proinflammatory cytokines and proteases, elastin breakdown, vascular smooth muscle cell (VSMC) apoptosis, and increased collagen turnover, macrophages are essential contributors to the pathogenesis of AAAs.2,3 Accordingly, monocytes/macrophages are reportedly activated by chronic inflammatory states, including atherosclerosis and oxidative stress, and by angiotensin II (Ang II) and inflammatory cytokines.Subsequently, macrophages infiltrate vessel walls, release proteases such as elastase, matrix metalloproteinase-12 (MMP-12) and metalloproteinases, and degrade extracellular matrix components such as collagen and elastin. 4,5 Simultaneously, infiltrating macrophages secrete inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interferon-γ, interleukin-1β, and interleukin-6, into the media and adventitia of aneurysmatic vessels, thereby, exacerbating inflammatory responses. 6Macrophage infiltration into vessel walls requires highly coordinated reorganization of actin cytoskeletal structures to create membrane protrusions called podosomes. 7 Human and murine podosomes contain many of the structural components

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“…The phosphorylation of p190RhoGAP has a direct effect on RhoA activity and increases the hydrolysis rate of GTP-bound RhoA, resulting in a smaller pool of activated RhoA (1,6,49), as observed in the Sam68 Ϫ/Ϫ MEFs. RhoA inactivation is not always observed with Src activation, as v-Src-transformed cells maintain elevated levels of active RhoA (4,69). Moreover, Src has been shown to regulate Rho GTPase activity by Rho GDP dissociation inhibitor (RhoGDI) phosphorylation and by decreasing the association of RhoGDI with Rho GTPases (19).…”

Section: Discussionmentioning

confidence: 99%

An Adaptor Role for Cytoplasmic Sam68 in Modulating Src Activity during Cell Polarization

Huot

Brown

Lamarche-Vane

et al. 2009

Molecular and Cellular Biology

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The Src-associated substrate during mitosis with a molecular mass of 68 kDa (Sam68) is predominantly nuclear and is known to associate with proteins containing the Src homology 3 (SH3) and SH2 domains. Although Sam68 is a Src substrate, little is known about the signaling pathway that link them. Src is known to be activated transiently after cell spreading, where it modulates the activity of small Rho GTPases. Herein we report that Sam68-deficient cells exhibit loss of cell polarity and cell migration. Interestingly, Sam68-deficient cells exhibited sustained Src activity after cell attachment, resulting in the constitutive tyrosine phosphorylation and activation of p190RhoGAP and its association with p120rasGAP. Consistently, we observed that Sam68-deficient cells exhibited deregulated RhoA and Rac1 activity. By using total internal reflection fluorescence microscopy, we observed Sam68 near the plasma membrane after cell attachment coinciding with phosphorylation of its C-terminal tyrosines and association with Csk. These findings show that Sam68 localizes near the plasma membrane during cell attachment and serves as an adaptor protein to modulate Src activity for proper signaling to small Rho GTPases.

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ERK5 promotes Src-induced podosome formation by limiting Rho activation

Cited by 47 publications

References 64 publications

MEK5 and ERK5 are mediators of the pro-myogenic actions of IGF-2

MEK5 and ERK5 are mediators of the pro-myogenic actions of IGF-2

Inhibition of KLF5–Myo9b–RhoA Pathway–Mediated Podosome Formation in Macrophages Ameliorates Abdominal Aortic Aneurysm

An Adaptor Role for Cytoplasmic Sam68 in Modulating Src Activity during Cell Polarization

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