Protein scaffolds in MAP kinase signalling

Brown, Matthew; Sacks, David B.

doi:10.1016/j.cellsig.2008.11.013

Cited by 208 publications

(167 citation statements)

References 87 publications

(132 reference statements)

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“…Recent studies have uncovered surprising dynamics within these complexes (Garbett and Bretscher, 2014). However, the mechanisms by which scaffolds control the ERK1/2 pathway are poorly understood (Bhattacharyya et al, 2006;Brown and Sacks, 2009;Good et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Spatial control of Shoc2 scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5

Jang

Shi

et al. 2015

Journal of Cell Science

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The scaffold protein Shoc2 accelerates activity of the ERK1 and ERK2 (ERK1/2, also known as MAPK3 and MAPK1) pathway. Mutations in Shoc2 result in Noonan-like RASopathy, a developmental disorder with a wide spectrum of symptoms. The amplitude of the ERK1/2 signals transduced through the complex is fine-tuned by the HUWE1-mediated ubiquitylation of Shoc2 and its signaling partner RAF-1. Here, we provide a mechanistic basis of how ubiquitylation of Shoc2 and RAF-1 is controlled. We demonstrate that the newly identified binding partner of Shoc2, the (AAA+) ATPase PSMC5, triggers translocation of Shoc2 to endosomes. At the endosomes, PSMC5 displaces the E3 ligase HUWE1 from the scaffolding complex to attenuate ubiquitylation of Shoc2 and RAF-1. We show that a RASopathy mutation that changes the subcellular distribution of Shoc2 leads to alterations in Shoc2 ubiquitylation due to the loss of accessibility to PSMC5. In summary, our results demonstrate that PSMC5 is a new and important player involved in regulating ERK1/2 signal transmission through the remodeling of Shoc2 scaffold complex in a spatially-defined manner.

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Section: Introductionmentioning

confidence: 99%

Spatial control of Shoc2 scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5

Jang

Shi

et al. 2015

Journal of Cell Science

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“…IQGAP1 is a widely expressed multidomain protein regulating different aspects of cell physiology and capable of binding to distinct signalling molecules (Brown and Sacks, 2006). Emerging evidence indicates that IQGAP1 acts as a scaffold for the MAPK cascade by binding b-Raf, MEK1/2 and ERK1/2, and regulating their activation in response to EGF in fibroblasts and epithelial cells (Brown and Sacks, 2009). We recently showed that IQGAP1 also acts as a scaffold of the MAPK pathway in the heart by binding to c-Raf, MEK1/2 and ERK1/2 (Sbroggiò et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1

Sbroggiò

Bertero

Velasco

et al. 2011

Journal of Cell Science

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SummaryExtracellular signal-regulated kinase 1/2 (ERK1/2) signalling is a key pathway in cardiomyocyte hypertrophy and survival in response to many different stress stimuli. We have previously characterized melusin as a muscle-specific chaperone protein capable of ERK1/2 signalling activation in the heart. Here, we show that in the heart, melusin forms a supramolecular complex with the proto-oncogene c-Raf, MEK1/2 (also known as MAPKK1/2) and ERK1/2 and that melusin-bound mitogen-activated protein kinases (MAPKs) are activated by pressure overload. Moreover, we demonstrate that both focal adhesion kinase (FAK) and IQ motif-containing GTPase activating protein 1 (IQGAP1), a scaffold protein for the ERK1/2 signalling cascade, are part of the melusin complex and are required for ERK1/2 activation in response to pressure overload. Finally, analysis of isolated neonatal cardiomyocytes indicates that both FAK and IQGAP1 regulate melusin-dependent cardiomyocyte hypertrophy and survival through ERK1/2 activation.

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“…Temporal and spatial control of MAPK signaling is regulated by protein scaffolds (17,18). Two proteins, PEA-15 and SEF, have been identified as cytoplasmic anchors for ERK2 (18).…”

Section: Discussionmentioning

confidence: 99%

Department of ENT, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P.R. China

et al. 2012

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Abstract. Mitogen-activated protein kinase phosphatase 5 (MKP-5)/DUSP10 acts as a phosphatase of stress-activated kinases (JNK and p38), but its activity towards ERK has not been demonstrated. In the present study we observed that MKP-5 interacts with ERK, retains it in the cytoplasm, suppresses its activation and downregulates ERK-dependent transcription. These data suggested a novel MKP-5 function as a scaffold protein for the ERK pathway. We analyzed MKP-5 gene expression in several tumors, and found that it is frequently upregulated in colorectal but not in lung and breast cancer, suggesting its association with the malignant phenotype of colon cancer.

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Protein scaffolds in MAP kinase signalling

Cited by 208 publications

References 87 publications

Spatial control of Shoc2 scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5

Spatial control of Shoc2 scaffold-mediated ERK1/2 signaling requires remodeling activity of the ATPase PSMC5

ERK1/2 activation in heart is controlled by melusin, focal adhesion kinase and the scaffold protein IQGAP1

Department of ENT, Nanfang Hospital, Southern Medical University, Guangzhou 510515, P.R. China

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