Reactome: A Curated Pathway Database

MAPK6/MAPK4 signaling

Stable Identifier
Homo sapiens
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MAPK6 and MAPK4 (also known as ERK3 and ERK4) are vertebrate-specific atypical MAP kinases. Atypical MAPK are less well characterized than their conventional counterparts, and are generally classified as such based on their lack of activation by MAPKK family members. Unlike the conventional MAPK proteins, which contain a Thr-X-Tyr motif in the activation loop, MAPK6 and 4 have a single Ser-Glu-Gly phospho-acceptor motif (reviewed in Coulombe and Meloche, 2007; Cargnello et al, 2011). MAPK6 is also distinct in being an unstable kinase, whose turnover is mediated by ubiquitin-dependent degradation (Coulombe et al, 2003; Coulombe et al, 2004). The biological functions and pathways governing MAPK6 and 4 are not well established. MAPK6 and 4 are phosphorylated downstream of class I p21 activated kinases (PAKs) in a RAC- or CDC42-dependent manner (Deleris et al, 2008; Perander et al, 2008; Deleris et al, 2011; De La Mota-Peynado et al, 2011). One of the only well established substrates of MAPK6 and 4 is MAPKAPK5, which contributes to cell motility by promoting the HSBP1-dependent rearrangement of F-actin (Gerits et al, 2007; Kostenko et al, 2009a; reviewed in Kostenko et al, 2011b). The atypical MAPKs also contribute to cell motility and invasiveness through the NCOA3:ETV4-dependent regulation of MMP gene expression (Long et al, 2012; Yan et al, 2008; Qin et al, 2008). Both of these pathways may be misregulated in human cancers (reviewed in Myant and Sansom, 2011; Kostenko et al, 2012)

Literature References
PubMed ID Title Journal Year
18593949 Steroid receptor coactivator-3/AIB1 promotes cell migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expression Cancer Res. 2008
22800433 Tumour promoting and suppressing roles of the atypical MAP kinase signalling pathway ERK3/4-MK5 J Mol Signal 2012
17161475 Atypical mitogen-activated protein kinases: structure, regulation and functions Biochim. Biophys. Acta 2007
18720373 Activation loop phosphorylation of the atypical MAP kinases ERK3 and ERK4 is required for binding, activation and cytoplasmic relocalization of MK5 J. Cell. Physiol. 2008
21329875 More, more, more: downregulation of a MK5-FoxO3a-mir34b/c pathway further increases c-Myc levels in colorectal cancer Mol. Cell 2011
18644862 The AIB1 oncogene promotes breast cancer metastasis by activation of PEA3-mediated matrix metalloproteinase 2 (MMP2) and MMP9 expression Mol. Cell. Biol. 2008
17947239 Modulation of F-actin rearrangement by the cyclic AMP/cAMP-dependent protein kinase (PKA) pathway is mediated by MAPK-activated protein kinase 5 and requires PKA-induced nuclear export of MK5 J. Biol. Chem. 2007
18248330 The Ser(186) phospho-acceptor site within ERK4 is essential for its ability to interact with and activate PRAK/MK5 Biochem. J. 2008
21177870 Activation loop phosphorylation of ERK3/ERK4 by group I p21-activated kinases (PAKs) defines a novel PAK-ERK3/4-MAPK-activated protein kinase 5 signaling pathway J. Biol. Chem. 2011
22505454 ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion J. Clin. Invest. 2012
20849292 Cross-talk between protein kinase A and the MAPK-activated protein kinases RSK1 and MK5 J. Recept. Signal Transduct. Res. 2011
15226418 N-Terminal ubiquitination of extracellular signal-regulated kinase 3 and p21 directs their degradation by the proteasome Mol. Cell. Biol. 2004
21372320 Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases Microbiol. Mol. Biol. Rev. 2011
12808096 Rapid turnover of extracellular signal-regulated kinase 3 by the ubiquitin-proteasome pathway defines a novel paradigm of mitogen-activated protein kinase regulation during cellular differentiation Mol. Cell. Biol. 2003
19166925 PKA-induced F-actin rearrangement requires phosphorylation of Hsp27 by the MAPKAP kinase MK5 Cell. Signal. 2009
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