Components of a New Human Protein Kinase Signal Transduction Pathway

Abstract

We have identified two components of a new protein kinase signaling cascade, MAPK/ERK kinase 5 (MEK5) and extracellular signal-regulated kinase 5 (ERK5). The MEK5 cDNA was isolated by degenerate PCR and encodes a 444-amino acid protein, which has approximately 40% identity to known MEKs. ERK5 was identified by a specific interaction with the MEK5 mutants S311A/T315A and K195M in the yeast two-hybrid system. The proteins were found to interact in an in vitro binding assay as well. ERK5 did not interact with MEK1 or MEK2. ERK5 is predicted to contain 815 amino acids and is approximately twice the size of all known ERKs. The C terminus of ERK5 has sequences which suggest that it may be targeted to the cytoskeleton. Sequences located in the N terminus of MEK5 may be important in coupling GTPase signaling molecules to the MEK5 protein kinase cascade. Both MEK5 and ERK5 are expressed in many adult tissue and are abundant in heart and skeletal muscle. A recombinant GST-ERK5 kinase domain displays autophosphorylation on Ser/Thr and Tyr residues.

Signaling by dual specificity kinases

“…Although, the functional signi®cance of this pathway in relation to other MKK-signaling pathway remains unclear, it is signi®cant to note here that p38MAPK and ERK2 can also phosphorylate and activate MEF2C. In this context, it is interesting to note that MKK5 and ERK5 are highly expressed in cardiac skeletal muscle (Zhou et al, 1995;English et al, 1995) while MEF2 family of transcription factors are mainly expressed in skeletal muscle and brain tissue (Martinet et al, 1994;McDermott et al, 1994). Taken together, these observation may be indicative of the critical role played by MKK5-ERK5 signaling pathway in cardiac physiology (Zhou et al, 1995).…”

“…Since JNK is also known as stress activated protein kinase (SAPK), a mouse homolog of MKK4/JNKK is known as SAPK/ERK kinase-1 or SEK1 (Sanchez et al, 1994). The dual speci®city kinase that phosphorylate ERK5 is known as MEK5 or MKK5 (Zhou et al, 1995;. The recently identi®ed dual speci®city kinase that speci®cally involved in the regulation of p38MAPK is known as MKK6 (Raingeaud et al, 1996;Moriguchi et al, 1996;Han et al, 1996;Stein et al, 1996).…”

“…A dual speci®city kinase kinase closely related to the other MKKs has been recently cloned from human fetal brain library and it is known as MKK5 (Zhou et al, 1995). Using the sequence of MKK5 in a yeast two-hybrid system identi®ed a novel downstream kinase, which is termed as ERK-5 or big MAP kinase (BMK).…”

Molecular cloning and characterization of a novel member of the MAP kinase superfamily

“…MOK contains the TEY motif, like the classical MAP kinases (ERK1 and 2), ERK5/BMK1 (Lee et al 1995;Zhou et al 1995), and ERK7 (Abe et al 1999). A sequence comparison of the kinase domain revealed that MOK is almost equally distant from each of the members of the MAP kinase superfamily (see Fig.…”

Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer

“…MAP kinase kinases (MEKs/MAPKKs) represent protein kinases upstream of MAPKs, critically controlling cellular proliferation and apoptosis. Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) is the most recently identified MAPKK and specifically activates ERK5, also known as Big MAP kinase 1 (English et al, 1995;Zhou et al, 1995). The ability of inhibitors of the classical MAPK (ERK1/2) cascade to block ERK5 activation suggested that ERK5 might regulate some cellular functions originally attributed to ERK1/2.…”