MAPK signalling in cellular metabolism: stress or wellness?

Abstract

Mitogen-activated protein kinase (MAPK) signalling occurs in response to almost any change in the extracellular or intracellular milieu that affects the metabolism of the cell, organ or the entire organism. MAPK-dependent signal transduction is required for physiological metabolic adaptation, but inappropriate MAPK signalling contributes to the development of several interdependent pathological traits, collectively known as metabolic syndrome. Metabolic syndrome leads to life-threatening clinical consequences, such as type 2 diabetes. This Review provides an overview of the MAPK-signalling mechanisms that underly basic cellular metabolism, discussing their link to disease.

Figure 1

Established and potential mechanisms of MAPK activation by the insulin receptor. (1) ERK activation through GRB2/SHC–SOS–Ras–Raf: SH2-domain-containing protein GRB2 binds to tyrosine-phosphorylated IRS or SHC and recruits SOS to activate Ras and in turn Raf–MEK–ERK. (2) JNK activation through PI3K: SH2-domain-containing PI3K regulatory subunits p85 activates MKK4 through a CDC42-dependent mechanism leading to activation of JNK. The mechanisms leading to p38 activation are unknown. CDC42, cell division cycle 42; ERK, extracellular-signal regulated kinase; GRB2, growth factor receptor-bound protein 2; GTP/GDP, guanosine-tri-(di)phosphate; IRS, insulin receptor substrate; JNK, Jun N-terminal kinase; MEK, MAPK/ERK kinase; MAPK, mitogen-activated protein kinase; MKK4/7, MAPK kinase 4/7; PI3K, phosphatidylinositol 3-kinase; PIP3/PIP2, phosphatidylinositol-tri-(di)phosphate; PKB, protein kinase B; SHC, Src homology 2 domain containing; SOS, son of sevenless.

Figure 2

Complex regulation of cellular metabolism by MAPKs. Cytokines (such as TNFα), insulin, other hormones (such as glucagon), growth factors (such as IGF1 or EGF) and environmental stress converge into MAPK signalling nodes that directly or indirectly—through MK2, MNK, MSK or p90^RSK—regulate numerous metabolic factors and processes. Only targets that are directly phosphorylated by the indicated kinases have been depicted. A more comprehensive list of targets and their functions, including references, can be found in supplementary Table 1 (online). ATF2, activating transcription factor 2; CREB, cAMP response element-binding protein; C/EBPα/β, CCAAT/enhancer binding protein-α/β; EGF, epithelial growth factor; EGFR, EGF receptor; elF4B/E, eukaryotic translation initiation factor-4B/E; FOXO1, forkhead box O1; GCGR, glucagon receptor; GR, glucocorticoid receptor; HSL, hormone sensitive lipase; IGF1, insulin growth factor 1; IGF1R, IGF1 receptor; IR, insulin receptor; MNK, MAPK-interacting kinase; mTORC1, mammalian target of rapamycin complex 1; MSK, mitogen- and stress-activated kinase; p90^RSK, p90 ribosomal S6 kinase; PGC1α, PPARγ co-activator-α; PPARα/γ, peroxisome proliferator-activated receptor-α/γ; SREBP1a/2, sterol regulatory element binding protein 1a/2; TNFα, tumour necrosis factor-α; TNFR, TNF receptor; TSC1/2, tuberous sclerosis complex 1/2.

Figure 3

Involvement of MAPK signalling in adipogenesis. Mesenchymal stem cells give rise to white and brown pre-adipocytes. After proper stimulation, distinct transcriptional pathways are initiated that ensure terminal differentiation of these precursors into adult white and brown adipocytes. Early upregulation of C/EBPβ and δ during white adipogenesis leads to activation of PPARγ and C/EBPα, which in turn regulate the expression of most genes responsible for triglyceride uptake and storage. PPARγ is also important for brown adipogenesis. However, the induction of additional genes such as PGC1α, helps to establish the brown adipocyte gene expression profile. MAPK signalling can regulate crucial events during both differentiation processes at different levels. ATF2, activating transcription factor 2; BMP2/7, bone morphogenic protein 2/7; C/EBPα/β/δ, CCAAT/enhancer binding protein α/β/δ; MAPK, mitogen-activated protein kinase; PGC1α, PPARγ co-activator 1 α; PPARγ, peroxisome proliferator-activated receptor γ; Pref1, pre-adipocyte factor 1; RA, retinoic acid; UCP1, uncoupling protein 1.