Abstract
MEK kinase 2 (MEKK2) is a 70-kDa protein serine/threonine kinase that has been shown to function as a mitogen-activated protein kinase (MAPK) kinase kinase. MEKK2 has its kinase domain in the COOH-terminal moiety of the protein. The NH(2)-terminal moiety of MEKK2 has no signature motif that would suggest a defined regulatory function. Yeast two-hybrid screening was performed to identify proteins that bind MEKK2. Protein kinase C-related kinase 2 (PRK2) was found to bind MEKK2; PRK2 has been previously shown to bind RhoA and the Src homology 3 domain of Nck. PRK2 did not bind MEKK3, which is closely related to MEKK2. The MEKK2 binding site maps to amino acids 637-660 in PRK2, which is distinct from the binding sites for RhoA and Nck. This sequence is divergent in the closely related kinase PRK1, which did not bind MEKK2. In cells, MEKK2 and PRK2 are co-immunoprecipitated and PRK2 is activated by MEKK2. Similarly, purified recombinant MEKK2 activated PRK2 in vitro. MEKK2 activation of PRK2 is independent of MEKK2 regulation of the c-Jun NH(2)-terminal kinase pathway. MEKK2 activation of PRK2 results in a bifurcation of signaling for the dual control of MAPK pathways and PRK2 regulated responses.
Highlights
MEK kinase 2 (MEKK2) is a 70-kDa protein serine/ threonine kinase that has been shown to function as a mitogen-activated protein kinase (MAPK) kinase kinase
MEKK2 is a MAPK kinase kinase that we have shown is activated in response to several extracellular stimuli including antigen receptors in T cells and mast cells and growth factors such as epidermal growth factor and Kit ligand [2, 3]
The findings suggested that Protein kinase C-related kinase 2 (PRK2) is capable of binding MEKK2
Summary
MEK kinase 2 (MEKK2) is a 70-kDa protein serine/ threonine kinase that has been shown to function as a mitogen-activated protein kinase (MAPK) kinase kinase. MEKK2 activation was required for its translocation because kinase-inactive MEKK2 was not recruited to the contact between the T cell and antigen presenting cell. Analysis of the NH2-terminal moiety of MEKK2 does not reveal an identifiable motif that has been defined in other proteins that are known to regulate protein-protein (i.e. SH3, prolinerich, etc.) or protein-lipid (i.e. pleckstrin homology domains) interactions. In an attempt to define the regulation of MEKK2 in antigen and growth factor responses, we have performed two-hybrid analysis to identify proteins that bind MEKK2. As we detail in this report, one binding partner that was identified in this screen was the protein kinase C-related kinase 2 (PRK2). Rho and Rac are involved in the regulation of cytoskeletal organization as well as many other cellular processes including membrane trafficking, activation of JNK and p38 MAPK pathways, transcription, cell growth, and development [13,14,15,16]. RhoB has been reported to mediate PKN association with endosomes [21]
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