ERK/MAPK signalling pathway and tumorigenesis

Abstract

Mitogen-activated protein kinase (MAPK) cascades are key signalling pathways that regulate a wide variety of cellular processes, including proliferation, differentiation, apoptosis and stress responses. The MAPK pathway includes three main kinases, MAPK kinase kinase, MAPK kinase and MAPK, which activate and phosphorylate downstream proteins. The extracellular signal-regulated kinases ERK1 and ERK2 are evolutionarily conserved, ubiquitous serine-threonine kinases that regulate cellular signalling under both normal and pathological conditions. ERK expression is critical for development and their hyperactivation plays a major role in cancer development and progression. The Ras/Raf/MAPK (MEK)/ERK pathway is the most important signalling cascade among all MAPK signal transduction pathways, and plays a crucial role in the survival and development of tumour cells. The present review discusses recent studies on Ras and ERK pathway members. With respect to processes downstream of ERK activation, the role of ERK in tumour proliferation, invasion and metastasis is highlighted, and the role of the ERK/MAPK signalling pathway in tumour extracellular matrix degradation and tumour angiogenesis is emphasised.

Keywords: ERK; Raf; Ras; cancer; extracellular signal-regulated kinase; mitogen-activated protein kinase; pathway; tumorigenesis.

Figure 1.

MAPK cascades. MAPKs, which are present in the cytoplasm and can be translocated into the nucleus, catalyse the phosphorylation of dozens of cytosolic proteins and numerous nuclear transcription factors. Adapted from (29). MAPK, mitogen-activated protein kinase; MAP4K, MAPK kinase kinase kinase; MAP3K, MAPK kinase kinase; MAPKK, MAPK kinase; MAPKAPK, mitogen-activated protein kinase-activated protein kinases; MEK, Ras/Raf/MAPK; RSK, ribosomal s6 kinase; MSK, mitogen- and stress-activated protein kinases; MNK, MAP kinase-interacting serine/threonine-protein kinases; cPLA2, cytosolic phospholipase A2; c-FOS, proto-oncogene c-Fos; Elk1, ETS domain-containing protein Elk-1; Ets1, Protein C-ets-1; SP-1, transcription factor Sp1.

Figure 2.

ERK MAPK signalling pathway. The kinase-mediated ERK MAPK signalling is sequentially activated by phosphorylation. ERK1/2 at the terminal kinases in MAPK signalling can translocate to the nucleus to regulate transcription programs, and mediate growth, migration and differentiation. The phosphorylated forms of MEK and ERK are indicated by white circles. Membrane Receptors are presented by grey shapes. Ligands are represented by white triangles. The cytoplasmic receptor is indicated by a thick black arrow. Adapted from (78,79). SOS, son of sevenless; GRB2, growth factor receptor-binding protein 2; p, phosphorylated.

Figure 3.

Downstream propagation direction of ERK1/2 kinase signalling in the ERK pathway. ERK1/2 is located in the cytoplasm of normal cells, while activated ERK1/2 is translocated to the nucleus to regulate the activity of transcription factors through phosphorylation. Cytoskeletal components are phosphorylated by ERK1/2 in the cytoplasm. Black arrows indicate signal propagation downstream of ERK. ‘Nuclear activities’ and ‘cytoplasmic activities’ depict ERK activation in the nucleus and cytoplasm, respectively. RSK, ribosomal s6 kinase; MSK, mitogen- and stress-activated protein kinases; MNK, MAP kinase-interacting serine/threonine-protein kinases; cPLA2, cytosolic phospholipase A2; MAP, microtubule-associated protein.

Figure 4.

Phosphorylation of upstream protein kinases in the ERK pathway. Curved arrows indicate the downstream targets of ERK. SOS, son of sevenless; GRB2, growth factor receptor-binding protein 2.

Figure 5.

Role of ERK/mitogen-activated protein kinase in cancer.