Mitogen-activated protein kinase (MAPK)-docking sites in MAPK kinases function as tethers that are crucial for MAPK regulation in vivo

2005

Signal transduction networks that regulate gene expression and metabolism are crucial for cell growth, differentiation, and survival. Accordingly, aspects of the pathology of many diseases result from defects in signaling pathways or the transcriptional responses they regulate (1).Many extracellular signals are transmitted to downstream targets by an evolutionarily conserved protein kinase cascade designated the mitogen-activated protein kinase (MAPK) 2 cascade. The MAPK (also known as extracellular-signal-regulated kinase, or ERK) cascade is a three-kinase module that transmits signals from cell-surface receptors to downstream targets through sequential phosphorylations (2). The MAPK is phosphorylated, and thereby activated, by an upstream MAPK/ERK kinase (MEK), which has previously been activated by a MEK kinase, such as the proto-oncoprotein Raf. To further propagate the signal, activated MAPKs phosphorylate other kinases such as RSK1 (3), which then regulate downstream effectors. In addition, MAPKs directly phosphorylate many key effectors, including the ubiquitous transcription factors Elk-1, Ets-1, and ATF-2 (4 -6).Tissue-specific transcription factors are also targets of MAPK phosphorylation and provide cell-type specificity to MAPK-regulated responses (7,8). The microphthalmia-associated transcription factor (MITF) is a tissue-specific MAPK substrate found in melanocytes. MITF is a master transcriptional regulator for melanocytes, coordinating the expression of genes involved in stem cell maintenance, differentiation, melanogenesis, and cell survival (9 -11). MITF haploinsufficiency leads to Waardenburg syndrome type IIa, which is characterized by deafness and pigmentation defects caused by melanocyte loss in the inner ear and the skin (12). In addition, dominant-negative mutations in MITF are associated with another auditory-pigmentary disorder, Teitz syndrome (13, 14) (reviewed in Ref. 15). MITF is also a potential target in the treatment of skin cancer, because it may impart a selective advantage to melanoma cells at low expression levels (16, 17), while having an antiproliferative effect at higher expression levels (18).During the differentiation of neural crest-derived melanocytes, activation of the c-Kit receptor tyrosine kinase by its ligand Steel factor initiates signaling through the Ras3 Raf3 MEK1/23 ERK1/2 cascade, resulting in the phosphorylation of MITF, and the consequent induction of genes involved in differentiation (e.g. p21 Cip1 (19)), melanogenesis (e.g. tyrosinase (20)), and melanocyte survival (e.g. Bcl2 (16)). ERK2 directly phosphorylates MITF on Ser 73 (21); MITF is also phosphorylated at Ser 409 by ERK-activated RSK1 (22). The dually phosphorylated MITF displays increased affinity for the transcriptional co-activator CREB-binding protein (23). Dually phosphorylated MITF is also targeted for ubiquitination and subsequent degradation, ensuring transient gene induction (22).The ability of MAPKs to effectively and specifically recognize their substrates is enhanced by their capacity t...

show abstract

Section: Methodsmentioning

confidence: 99%

Characterization of an ERK-binding Domain in Microphthalmia-associated Transcription Factor and Differential Inhibition of ERK2-mediated Substrate Phosphorylation

Molina

Grewal

2005

show abstract

“…Finally, other kinases, as exemplified by mitogen-activated protein kinases (MAPKs), bind directly to short docking motifs on substrates that are located at various distances from the target phosphosite (4, 5, 9 -11). These docking interactions are thought to dynamically tether the catalytic domain within range of appropriate target sites (12). There is increasing interest in targeting docking interactions as a possible drug development strategy (13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Two Hydrophobic Residues Can Determine the Specificity of Mitogen-activated Protein Kinase Docking Interactions

2015

Background: MAPK cascade proteins bind to each other selectively via docking interactions. Results: The high selectivity of JNK family MAPKs for cognate binding partners is controlled by two key hydrophobic residues in the docking site. Conclusion: This contrasts with other proposed models of docking specificity. Significance: This has implications for drug design and for the evolution of signaling specificity.

show abstract

“…D-sites in MKKs are crucial for the activation of their cognate MAPKs in vivo (44,45), where they function as portable, modular motifs that primarily serve to tether their cognate MAPKs near the kinase domain of MKKs (45). D-sites also display some selectivity in binding to MAPKs, suggesting a role in specificity (40,46).…”

mentioning

confidence: 99%

Interacting JNK-docking Sites in MKK7 Promote Binding and Activation of JNK Mitogen-activated Protein Kinases

Ho¹,

Grewal³

et al. 2006