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Map Kinase Cascades

The Mitogen-activated protein kinases (MAP Kinases) are a group of protein serine/threonine kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. In combination with several other signaling pathways, they can differentially alter phosphorylation status of the transcription factors. A controlled regulation of these cascades is involved in cell proliferation and differentiation, whereas an unregulated activation of these MAP kinases can result in oncogenesis.

Three major types of MAP kinase cascades have been reported in mammalian cells that respond synergistically to different upstream signals. The most widely studied cascade is that of ERK1/ERK2 MAP kinases. A general activation scheme involves the activation of receptor tyrosine kinases by growth factors, such as EGF, which provides the binding site of the adapter protein Grb2 that in turn localizes Sos to the plasma membrane. Sos activates Ras by exchange of GTP for GDP. The Ras-GTP binds directly to a serine-threonine kinase, Raf, forming a transient membrane-anchoring signal. Active Raf kinase phosphorylates a dual specificity kinase, MEK, on serine²¹⁸ and serine²²² and activates it. MEK can also be phosphorylateld by Mos, a protein kinase expressed during meiotic maturation of oocytes and by MEKK1. A generally held belief is that MEK1 binds ERK and phosphorylates either a threonine or a tyrosine residue and then dissociates. The monophosphorylated ERK then rebinds to an active MEK1 for dual phosphorylation and complete activation. The activated MEK phosphorylates ERK1/ERK2 on threonine183 and tyrosine185 (at the TEY motif). The major targets of activated ERKs are pp90 ribosomal S6 kinase (Rsk) and the cytoplasmic phospholipase A₂. ERK also translocates to the nucleus to phosphorylate transcription factor Elk-1 (on serine³⁸³ and serine³⁸⁹). Usually only one highly active form of ERK1 or ERK2 (dual phosphorylated) exists in the cell which exhibits over 1000-fold greater activity than the unphosphorylated form. With in the cell, at any time, one may find three low active forms of ERKs: one unphosphorylated enzyme, and two singly phosphorylated forms that contain phosphate either at the tyrosine or threonine residue.

Recently, another related kinase, ERK3, a nuclear protein kinase, has been cloned and is reported to exhibit about 50% homology to ERK1/ERK2 within its catalytic domain. However, it does not phosphorylate any typical ERK substrates. The phosphorylation site motif in the activation loop of ERK3 has a single phosphorylation site located at serine189. Another member of ERK family is the ERK5 that contains at least ten consensus sites for MAP kinase phosphorylation and may be associated with keeping ERK5 in high active state. ERK5 is believed to affect the phosphorylation of MADS box transcription factors, ETS-like transcription factor SAP1a, and myocyte enhancer factor 2A and C.

The second most widely studied MAP kinase cascade is the JNK/SAPK (c-Jun kinase/stress activated protein kinase). This cascade is activated following exposure to UV radiation, heat shock, or inflammatory cytokines. The activation of these MAP kinases is mediated by Rac and cdc42, two small G-proteins. The activated cdc42 binds to PAK65 protein kinase and activates it. The activated PAK65 can activate MEKK, which in turn phosphorylates SEK/JNKK at serine²¹⁹ and serine²²³ and activates it. The active SEK/JNKK phosphorylates JNK/SAPK (at the TPY motif) that in turn binds to the N-terminal region of c-Jun and phosphorylates it at serine⁶³ and serine⁷³. The sites of activating phosphorylation are conserved between ERK and JNK, however, these sites are located within distinct dual specificity phosphorylation motifs (TPY for JNK and TEY for ERK). Molecular cloning studies show about 40-45% sequence homology between JNK/SAPK and the classical MAP kinases.

The p38 kinase is the most well-characterized member of the MAP kinase family. It is activated in response to inflammatory cytokines, endotoxins, and osmotic stress. It shares about 50% homology with the ERKs. The upsteam steps in its activation of this cascade are not well defined. However, downstream activation of p38 occurs following its phosphorylation (at theTGY motif) by MKK3, a dual specificity kinase. Following its activation, p38 translocates to the nucleus and phosphoryates ATF-2. Another known target of p38 is MAPKAPK2 that is involved in the phosphorylation and activation of heat-shock proteins.

Although different MAP kinase cascades show high degree of specificity and functional separation, some degree of cross-talk is observed between different pathways. For example, JNKK, an activator of JNK/SAPK, is reported to activate p38, whereas MKK3 activates only p38 and not JNK/SAPK. MEKK1 that stimulates SEK/JNKK1 in the JNK/SAPK cascade has only a trivial effect on p38 activation. In the upstream signaling, Sos stimulates only the ERK pathways without affecting either JNK or p38 cascade. Another important observation is that in mammalian cells are treated with mitogenic agents, ERKs are significantly activated whereas JNK/SAPK are not affected. Conversely, cells exposed to stress cells activate JNK/SAPK pathway without altering the activity of ERKs. At the transcription level, ATF-2 is phosphorylated and activated by all three MAP kinases, whereas c-Jun and Elk-1 are phosphorylated by ERKs and JNK/SAPK, yet all these pathways result in transcriptional activity that is unique for a particular external stress.

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MAPK: Mitogen-activated protein kinase; ERK: Extracellular signal regulated kinase; JNK: Jun N-terminal kinase; SAPK: Stress-activated protein kinase; MEK: MAPK/ERK Kinase; MEKK: MEK kinase; JNKK: JNK kinase; MAPKAPK: MAPK-activated protein kinase; RK: Reactivating kinase; SEK: SAPK kinase

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