Mitogen-activated protein kinase kinase kinase kinase 5, also known as Kinase homologous to SPS1/STE20, MAPK/ERK kinase kinase kinase 5, MEK kinase kinase 5 and MAP4K5, is a cytoplasm protein which belongs to the ,protein kinase superfamily, STE Ser/Thr protein kinase family and STE20 subfamily. MAP4K5 is ubiquitously expressed in all tissues examined, with high levels in the ovary, testis and prostate. It contains one ,CNH domain and one ,protein kinase domain. MAP4K5 is highly similar to yeast SPS1/STE20 kinase. Yeast SPS1/STE20 functions near the beginning of the MAP kinase signal cascades that is essential for yeast pheromone response. MAP4K5 has been shown to interact with CRKL and TRAF2. This kinase was shown to activate Jun kinase in mammalian cells. MAP4K5 is an early component of MAP kinase signal cascades. It may play a role in the response to environmental stress. MAP4K5 appears to act upstream of the JUN N-terminal pathway.
ERK3, also known as MAPK12 and p38-gamma, belongs to the ,protein kinase superfamily, CMGC Ser/Thr protein kinase family and MAP kinase subfamily. ERK3 is highly expressed in skeletal muscle and heart. ,ERK3 is a serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.
The p38 family of mitogen-activated protein kinases (MAPK) includes p38 alpha (SAPK2a, CSBP), p38 beta (SAPK2b), p38 delta (SAPK4), and p38 gamma (SAPK3/ERK6). p38 alpha and p38 beta are widely expressed p38 isoforms that are involved in regulation of cell proliferation, differentiation, development, and response to stress. p38 delta, also known as MAPK13, is a regulator of differentiation-dependent gene expression in keratinocytes, and been as a regulator of surface epithelia differentiation and apoptosis. p38 delta protein is upregulated in Cholangiocarcinoma (CC) relative to hepatocellularcarcinoma (HCC) and to normal biliary tract tissues. p38 delta is important for motility and invasion of CC cells, suggesting that p38 delta may play an important role in CC metastasis. p38 delta is expressed in the epidermis, suggesting a role for p38 delta in regulating differentiation. p38 delta is the major p38 isoform driving suprabasal involucrin gene expression and that p38 delta directly regulates ERK1/2 activity via formation of a p38 delta-ERK1/2 complex. Recent emerging evidence suggests that the p38 stress MAPK pathway may function as a tumor suppressor through regulating Ras-dependent and-independent proliferation, transformation, invasion and cell death by isoform-specific mechanisms. p38 delta has important role in promoting cell proliferation and tumor development in epidermis and may have therapeutic implication for skin cancer.
The p38 Mitogen-activated Protein Kinases (MAPKs) are a family of four related Ser/Thr kinases activated by proinflammatory cytokines and environmental stresses, such as UV irradiation and heat shock. Stress signals are delivered to this cascade by members of small GTPases of the Rho family (Rac, Rho, Cdc42). p38 MAPK is involved in the regulation of Hsp27 and MAPKAP-2 and several transcription factors including ATF2, STAT1, and indirectly CREB via activation of MSK1. The p38 MAPK protein also plays a role in cell differentiation, autophagy and apoptosis. Mkk3 and SEK can activate p38 MAPK by phosphorylation at Thr180 and Tyr182, which in turn activates the MAPKAP kinase 2 and regulating phosphorylation of ATF2, Mac and MEF2.
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