The ERK Module

In mammals, the prototypical MAPKs are encoded by two genes, Erk-1 and -2, generating proteins of 44 and 42 kDa, respectively [2]. Like most of the MAPK proteins, these enzymes are widely expressed and are generally not regulated at the transcriptional level. These enzymes are phosphorylated and activated by MAPK/ERK kinases (MEKs) 1 and 2, which target a threonine and a tyrosine residue within the T-loop of the kinase domain [10,11].

Handbook of Cell Signaling, Volume 1

Figure 1 Mammalian MAPK modules. The MAPK module consists of a MAPKKK, MAPKK, and a MAPK. These pathways respond to extracellular signals, including growth factors, hormones, cell stresses, and cytokines. Once activated, MAPKs can phosphorylate a wide variety of proteins, including transcription factors and other kinases. See text for details.

Figure 1 Mammalian MAPK modules. The MAPK module consists of a MAPKKK, MAPKK, and a MAPK. These pathways respond to extracellular signals, including growth factors, hormones, cell stresses, and cytokines. Once activated, MAPKs can phosphorylate a wide variety of proteins, including transcription factors and other kinases. See text for details.

When phosphorylated, this loop swings out, allowing adenosine triphosphate (ATP) and substrate to access the catalytic pocket [6]. MEK activity is similarly dependent upon phosphorylation at two T-loop serine residues by upstream kinases, typically Rafl but also B-Raf, Mos, or MEKK1 [12].

The availability of phospho-specific antibodies selective for the T-loop phosphorylation sites of ERKs and MEKs has simplified monitoring of the modification of these enzymes following cellular stimulation. Perhaps unexpectedly, such studies have shown that the triad of protein kinases that lead to MAP activation does not function as an amplification circuit, as occurs, for example, in cAMP-dependent activation of glycogen phosphorylase. Instead, the three kinases appear to interact in a one-to-one linear system. So why invest in three kinases when one could do the same job? The answer may lie in the exquisite levels of regulation and sensitivity that are made possible by this arrangement, as well as enhanced specificity. For example, work by Ferrell and colleagues in Xenopus has revealed that the MAPK and JNK/SAPK pathways act like switches [13,14]. A stimulus triggers a binary response, on or off with nothing in between. The effect is termed bistability and relates to the quantum change required to overcome the activation hurdle (which is opposed by different phosphatases acting on the various MAPK triad components). In yeast, there is another rationale for the three-kinase module. In this case, the same three components can be utilized in different responses, depending on their association with the STE5 scaffolding protein [15]. STE5 acts to insulate the MAPK module by cloistering the kinases together such that they are functionally coupled to a particular stimulus. Loss of STE5 releases the STE11 MAPKKK, which can then couple to a MAPK module activated by hyperosmolarity. Such clustering of signaling molecules is now recognized as a common means to achieve specificity and to counter entropic forces that tend to equalize cellular protein distribution.

Substrates of ERKs include additional protein kinases such as MAPKAP-kinase, signaling molecules such as phos-pholipases, and transcription factors such as Elk-1/ternary complex factor [9]. These and other ERK targets share an ERK phosphorylation motif minimally comprised of Pro-X-Ser/Thr-Pro, although high-affinity substrates usually harbor additional binding interfaces for the kinase. Online databases such as Scansite [16] are useful tools that use such consensus sequences to predict phosphorylation sites (and the corresponding kinases that modify them) within any protein.

ERK activation is often associated with proliferation (for example, Raf induction is tightly coupled to growth-induced or oncogenic Ras activation), but the consequences of ERK stimulation depends on the signal and cell type. Even in the same type of cell, the kinetics of ERK activation play a defining role in the ultimate response. For example, in PC12 pheochromocytoma cells, slow but sustained ERK activation by nerve growth factor induces neurite outgrowth and differentiation. By contrast, short but sharp activation of the same pathway by epidermal growth factor results in cell proliferation [17]. Thus, the same signaling machinery can deliver different messages within a cell.

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