MAPK signaling pathway

These pathways regulate key processes such as cell proliferation, differentiation, and apoptosis in various eukaryotes. In mammalian cells, three distinct families of MAPKs have been characterized: classical MAPK (ERK), C-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 kinase¹. Specific extracellular signals trigger each cascade and lead to the activation of a particular MAPK following the successive activation of a MAPK kinase kinase (MAPKKK) and a MAPK kinase (MAPKK). The MAPKKK is usually activated by interactions with a small GTPase and/or phosphorylation by protein kinases downstream from cell surface receptors. The MAPKKK phosphorylates and activates MAPKK, activating MAPK via dual phosphorylation of a conserved tripeptide TxY motif in the activation region. When activated, the MAPK phosphorylates various substrates in the cytosol and the nucleus, modifying protein functions and gene expression to produce the appropriate biological response.

Members of the ERK family are characterized by a TEY motif in their activation segment and can be divided into two major groups: classic ERKs and larger ERKs. The classic ERKs, which include ERK1 and ERK2, consist primarily of a kinase domain. In contrast, larger ERKs, such as ERK5, have a significantly extended sequence at the carboxy-terminal end of their kinase domain. The classic ERK1/2 module mainly responds to growth factors and mitogens, promoting cell growth and differentiation. Key upstream regulators of this module include cell surface receptors, such as receptor tyrosine kinases (RTKs), G-protein-coupled receptors (GPCRs), and integrins, along with small GTPases like Ras and Rap. The MAPKKs associated with the classic ERK1/2 module are MEK1 and MEK2, while the upstream MAPKKKs include members of the Raf family, along with Mos and Tpl2.

JNK family members, including JNK1, JNK2, and JNK3, contain a TPY motif in their activation segment. The JNK module is activated by various environmental stresses such as ionizing radiation, heat, oxidative stress, and DNA damage, as well as by inflammatory cytokines and growth factors. Signaling to the JNK module often involves Rho family GTPases, specifically Cdc42 and Rac. This module is critical in apoptosis, inflammation, cytokine production, and metabolism. The MAPKKs linked with the JNK module are MKK4 and MKK7, while the upstream MAPKKKs include MEKK1, MEKK4, MLK2, MLK3, ASK1, TAK1, and Tpl2.

The p38 family consists of members that possess a TGY motif in the activation segment, including p38α, p38β, p38γ, and p38δ. Similar to JNK modules, p38 modules are highly triggered by environmental stresses and inflammatory cytokines. The activation of p38 plays a crucial role in inflammation, apoptosis, cell differentiation, and cell cycle regulation. The primary MAPKKs for p38 modules are MKK3 and MKK6, while the MAPKKKs include MLK2, MLK3, MEKKs, ASKs, TAK1, and TAO1 and TAO2. Key substrates in p38 signaling include downstream kinases such as MK2/3, PRAK, MSK1, and MSK2, along with various transcription factors².

Specific scaffold proteins interacting with at least two core kinases within each MAPK module have been identified. These scaffolds play a significant role in MAPK signaling by enhancing the local concentration of the components, providing spatial and temporal regulation of cascade activation, and localizing the module to specific cellular sites or substrates.

This MAPK pathway poster explores the key roles of these proteins in regulating fundamental processes within mammalian cells. They are intricately connected to other signal transduction systems via shared substrates and cross-cascade interactions.

References

1. Zhang, W. & Liu, H. MAPK signal pathways regulate cell proliferation in mammalian cells. Cell Res.   12, 9–18 (2002).

2. Morrison, D. K. MAP kinase pathways.  Cold Spring Harb Perspect Biol   4, a011254 (2012).