EGFR protein – Epidermal growth factor receptor(EGFR)

General information on EGFR protein

Heat shock 70 kDa protein 1 (HSPA1A), also known as Hsp72, is a member of heat shock protein 70 family. HSPA1A acts as chaperone protein and facilitates the proper folding of newly translated and misfolded proteins in organelles and cytosol. It also stabilizes or degrades mutant proteins. In addition, HSPA1A protein is involved in DNA reparation. Due to these functions, HSPA1A contributes to biological processes such as cell growth, cell differentiation, apoptosis, protein homeostasis, signal transduction and so on.
HSPA1A protein has a C-terminal substrate-binding domain and a N-terminal ATP-binding domain. The substrate binding domain has two subdomains; an α-helical subdomain and a two-layered β-sandwich subdomain (SBDβ). The peptide binding pocket is within SBDβ while SBDα covers the substrate binding cleft. As for ATP binding domain, it consists of four distinct subdomains split into two lobes by a central ATP/ADP binding pocket. The two terminal domains are linked together by a LL loop region referred to as loop LL. The latter is essential for allosteric regulation. At the very end of the C-terminal, there is an unstructured region which is believed to be the docking site for co-chaperones.
As a member of Hsp70 protein family, HSPA1A is an important apoptotic constituent by default. Hsp72 acts on a caspase-dependent pathway that eventually leads to inhibition of cell apoptosis. It also acts against apoptosis-inducing agents such as tumor necrosis factor α (TNfα), staurosporine and doxorubicin. Since deregulation of cell apoptosis are linked to many pathological processes, it is no surprise that Hsp72 is involved in the development and progression of several diseases. For instance, overexpression of Hsp72 has been linked to gastric cancers, breast cancers, lung cancers and so on. Research data (Wang et al., 2013) showed that elevated levels of HSPA1A in tumor cells may increase malignancy and resistance to anti-cancer therapy.

EGFR protein also known as epidermal growth factor receptor, ErbB-1 or HER1 is a transmembrane protein member of the ErbB family of receptors. It acts as a receptor for epidermal growth factor family members (EGF family) such as EGF (epidermal growth factor) and TGFα (transforming growth factor α). Upon ligand binding, EGFR undergoes transition from a monomer in the inactive form to a homodimer in the active form. In addition to forming homodimers, EGFR can also form heterodimers by pairing with other members of ErbB family of receptors. The dimerization step is key for its intrinsic protein-tyrosine kinase activity which results in the autophosphorylation of several tyrosine (Y) residues in the C-terminal domain. Once phosphorylated, it recruits adaptor proteins such as GRB2 which, in turn, elicits a series of signaling and activation pathways that modulate cell migration, adhesion and proliferation. It is believed that the EGFR phosphorylates directly other proteins such as RGS16 which activates its GTPase activity. Furthermore, EGFR protein phosphorylates MUC1 which is a glycoprotein that contains an extensive O-linked glycosylation on its extracellular domain. MUC1 induced phosphorylation results in an increased interaction with SRC and CTNNB1/beta-catenin. The downstream signaling enhances other transduction cascade such as the MAPK, Akt, JNK and RAS-RAF-MEK-ERK pathways. It is worth mentioning that EGFR can also cross-phosphorylate the tyrosine residues of the other receptor with which it form the heterodimer.

Given its importance in key cellular functions, the activity of EGFR protein is highly regulated. For instance, the activation of EGFR can be inhibited by phosphatases like PTPRJ and PTPRK complexes that constitute an immediate regulatory mechanism. The EGF ligand binding also induces the phosphorylation of EPS15 complex which regulate EGFR activity. Other feedback inhibitors include SOCS4, SOCS5, LRIG1 and ERRFI1 protein.

Deficient EGFR signaling pathway has been linked to diseases such as Alzheimer’s, Its overexpression is believed to be associated with the development different types of tumors.