MP1: A MEK Binding Partner That Enhances Enzymatic Activation of the MAP Kinase Cascade

Abstract

Signal transduction is controlled both by regulation of enzyme activation and by organization of enzymatic complexes with nonenzymatic adapters, scaffolds, and anchor proteins. The extracellular signal-regulated kinase (ERK) cascade is one of several evolutionarily conserved mitogen-activated protein (MAP) kinase cascades important in the regulation of growth, apoptosis, and differentiation. A two-hybrid screen was conducted to identify nonenzymatic components of this signaling cascade that might be important in regulating its activity. A protein called MP1 (MEK Partner 1) was identified that bound specifically to MEK1 and ERK1 and facilitated their activation. When overexpressed in cultured cells, MP1 enhanced activation of ERK1 and activation of a reporter driven by the transcription factor Elk-1. Expression of MP1 in cells increased binding of ERK1 to MEK1. MP1 apparently functions as an adapter to enhance the efficiency of the MAP kinase cascade.

Interferon-α 2b reduces phosphorylation and activity of MEK and ERK through a Ras/Raf-independent mechanism

“…A specific phosphatase -such as PP2A (Anderson et al, 1990) -may be induced by IFN-α, thus resulting in the inactivation of MEK or ERK. Another possibility is that IFN-α may regulate the expression of docking proteins (Pawson and Scott, 1997;Schaeffer et al, 1998;Whitmarsh and Davis, 1998), eventually affecting the interaction between MEK and ERK, or between MEK and upstream kinases. Understanding the exact mechanism is important for our comprehension of the proper function of IFN-α and possibly to develop novel targets to strengthen the IFN-mediated anti-cancer effect.…”

From receptors to stress-activated MAP kinases

“…Examples of this have been identi®ed in S. cerevisiae, and recently in mammals (Schae er et al, 1998;Whitmarsh et al, 1998). JNK interacting protein (JIP1) selectively binds to MKK7 (MAPKK), MLK3 (MAPKKK) and HPK (MAPKKKK), thereby enhances the e ciency and speci®city of enzyme-substrate interactions (Whitmarsh et al, 1998).…”

Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: A perspective

“…Our recent observations have suggested a potential role for the MP1-p14 complex in coupling MAP kinase signaling to Rho [126]. MP1 is a small protein (14 kDa) identified as a MEK1 and ERK1 binding partner [127]; p14 is a protein tightly associated with late endodomes and lysosomes that was subsequently found to interact with high affinity with MP1 [128][129][130]. Specifically, we have found that MP1-p14 is important for PAK phosphorylation of MEK1 and ERK activation during adhesion to fibronectin, and that siRNA-mediated depletion of the complex causes a spreading defect in fibroblasts in concert with the formation of dense circumferential F-actin and large vinculin containing adhesions [126].…”

“…One intriguing possibility is that MP1/p14 may incorporate into the dynein motor complex through the LC7-like motif in p14 and thus tether MEK1, ERK1 and PAK1 to the dynein motor complex on microtubules. Since MP1 binds preferentially to inactive MEK1 [127] and active PAK1 [126], one might speculate that MP1/ p14 could serve to integrate MEK and PAK signals into the microtubule and motor machinery. Alternatively, PAK1 bound to DLC1 through PAK1 N-terminus, might bridge the MP1/p14 dimer bound to its C-terminus to molecular motors on microtubules facilitating specific targeting to cellular sites of action (Fig.…”

“…Even though no mammalian protein shares significant sequence similarity with Ste5, the disparate binding functions of Ste5 may be distributed among several scaffolding proteins in mammals [127]. For example, MORG binds MP1, MEK and ERK and might regulate ERK activation in response to GPCR signaling [225], whereas MP1/p14 might be involved in select set of growth factor signaling and integrin signaling responses [126,225].…”