Development - ERK5 in cell proliferation and neuronal survival

ERK5 in cell proliferation and neuronal survival

Mitogen-activated protein kinase 7 (ERK5 (MAPK7)) is involved in regulation of various cellular processes first of all cell proliferation and survival. ERK5 (MAPK7) is a mitogen-activated protein kinase regulated by a wide range of mitogens and cellular stresses [1].

Epidermal growth factor (EGF) and Nerve growth factor (NGF) could activate ERK5 (MAPK7) through Ras-dependent mechanism. Harvey rat sarcoma viral oncogene homolog (H-Ras) activation triggers the Raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 5 (MAP2K5 (MEK5))/ ERK5 (MAPK7) pathway. Subsequently ERK5 (MAPK7) phosphorylates and activates Elk-4. Elk-4 activates FBJ murine osteosarcoma viral oncogene homolog (c-Fos) transcription leading to cell proliferation [2], [3].

NGF binding to its receptor Neurotrophic tyrosine kinase, receptor, type 1 (TrkA) stimulates Sequestosome 1(p62) binding to TrkA. Sequestosome 1(p62) -TrkA interaction is required for the internalization of the receptor followed by activation of atypical PKCs: PKC-zeta and PKC-lambda/iota. Atypical PKCs bind to (MAP2K5 (MEK5)) but they are unable to directly phosphorylate MAP2K5 (MEK5) and activate this kinase most likely by promoting its autophosphorylation. MAP2K5 (MEK5) is essential activator of ERK5 (MAPK7). Activation of ERK5 (MAPK7) through atypical PKCs leads to Myocyte enhancer factor 2C (MEF2C) phosphorylation and activation by ERK5 (MAPK7). MEF2C activates Jun oncogene (c-Jun) transcription which is essential component in proliferative signaling [4], [5].

Brain-derived neurotrophic factor (BDNF) activates cascade by Rap1-dependent mechanism and signals to neuronal survival. ERK5 (MAPK7) provides neuronal survival through cAMP responsive element binding protein 1 (CREB1) phosphorylation and activation which is probably mediated by Ribosomal protein S6 kinase, 90kDa, polypeptide 3 (p90RSK2(RPS6KA3)) [6], [7].

Stress (such as H2O2 application) activates Lymphocyte-specific protein tyrosine kinase (Lck) which in turn phosphorylates and activates SH2 domain protein 2A (TSAD). TSAD binds to Mitogen-activated protein kinase kinase kinase 2 (MAP3K2 (MEKK2)) activates it and triggers MAP3K2 (MEKK2)/ MAP2K5 (MEK5)/ ERK5 (MAPK7) cascade. TSAD is also involved in activation of mentioned cascade by EGF but exact mechanism isn't clear [8], [9].

Apart pathways regulated by stress and growth factors ERK5 (MAPK7) activity is stimulated by WNK lysine deficient protein kinase 3 (WNK) through phosphorylation and activation of MAP3K2 (MEKK2) and Mitogen-activated protein kinase kinase kinase 3 (MAP3K3). Though upstream activators of WNK for this pathway are yet unknown [10].

References:

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   Contribution of the ERK5/MEK5 pathway to Ras/Raf signaling and growth control. The Journal of biological chemistry 1999 Oct 29;274(44):31588-92
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   Brain-derived neurotrophic factor activates ERK5 in cortical neurons via a Rap1-MEKK2 signaling cascade. The Journal of biological chemistry 2006 Nov 24;281(47):35965-74
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   MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway. The Journal of biological chemistry 2001 Feb 16;276(7):5093-100
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   MEK kinase 2 and the adaptor protein Lad regulate extracellular signal-regulated kinase 5 activation by epidermal growth factor via Src. Molecular and cellular biology 2003 Apr;23(7):2298-308
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    WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. The Journal of biological chemistry 2004 Feb 27;279(9):7826-31