Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways

Abstract

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors.

Keywords: AKT; ERK; ErBB; G1; cell cycle; cell proliferation; epidermal growth factor receptor; signal transduction.

Figure 1

Epidermal growth factor receptor (EGFR) signaling pathways leading to G1/S cell cycle progression activated by EGF activation. Depicted are the RAS-RAF-MEK-ERK MAPK and PI3K-AKT-mTOR pathways. EGF activation of the EGFR induces receptor dimerization and transphosphorylation of the C-terminal domain. The phosphorylated C-terminal domain binds SHC and GRB2, along with PLC-γ1 at Y992 (not pictured). The GRB2 SH3 domain recruits the proline-rich domains of SOS or GAB1 to initiate ERK MAPK or AKT signaling respectively. SOS is also recruited to the plasma membrane (PM) by the interaction of its PH (pleckstrin homology) domains with PIP₂ (phosphatidylinositol-4,5-bisphosphate) and PA (phosphatidic acid). SOS catalyzes the conversion of GDP to GTP of RAS. Active RAS uses its RAS RAF-binding domain (RBD) to recruit RAF-1. RAF-1 is activated by dephosphorylation and phosphorylation events, and activates MEK1/2. Activated MEK1/2 activates ERK1/2. ERK1/2 has various cytoplasmic and nuclear targets, which aid in the transcription and translation of Cyclin D1. For example, ELK-1 transcribes the c-FOS gene (not pictured), and the protein product together with c-JUN make up the AP-1 complex. The AP-1 complex as well as c-MYC induce the transcription of CYCLIN D1. On the other hand, the receptor-bound GRB2 also binds GAB1. GAB1 recruits the p85 regulatory subunit of PI3K, which binds the p110 catalytic subunit. PI3K converts PIP₂ into PIP₃ (phosphatidylinositol-3,4,5-triphosphate). PIP₃ recruits AKT, and is phosphorylated and activated by PDK1 and mTORC2. AKT has many phosphorylation substrates, including various inhibitory phosphorylations to proteins that negatively regulate CYCLIN D1 activity such as GSK-3β (normally induces CYCLIN D1 degradation) and FOXO (normally represses CYCLIN D1 transcription). Furthermore, AKT inhibition of TSC2 allows the activation of mTOR, which inhibits the inhibitor of translation 4E-BP, thus allowing eIF4E-mediated translation of CYCLIN D1. Increased levels of CYCLIN D1 correlates with increased CDK4/6 activity, which phosphorylates RB. Phosphorylated RB releases the E2F transcription factor, which participates in the transcription of Cyclin E and leads to G1/S progression. The CDK inhibitor protein p27 inhibits CYCLIN D-CDK4/6 activity. However, activated ERK, c-MYC, AKT, all inhibit p27 activity. Importantly, the activated ERK MAPK and AKT pathways also inhibit various pro-apoptotic proteins, including BIM, Caspase-9, and BAD.