Cell Signalling – Mini Review

Cell signalling pathways have an important role in integrating a plethora of extracellular and intracellular signals to produce a controlled optimal output of signals, and results in the regulation of specific cellular responses. This is crucial for the homeostasis of the cell, and the deregulation of signalling pathways has been related to a number of diseases including cancer (Choudhary and Mann 2010). 

Cells integrate signals from the extracellular matrix by expressing specific receptors on the plasma membrane that can be activated by a specific ligand. Receptors then transduce the extracellular signal through a myriad of cell signalling pathways, involving adapter proteins, kinases and protein scaffolds resulting in a biological response (Hofer et al. 2004). Extracellular signals are transduced by cell membrane receptors, which results in a cellular response. Cytokine receptors play a key role in regulating the haematopoietic system and integrating immune responses (Fernandez-Botran 1991).

Cytokines regulate proliferation, cell death and cell survival, and their effects are regulated by specific cytokines binding to specific cytokine receptors (Bazan 1990). Receptor tyrosine kinases are activated by extracellular ligands and binding of these ligands results in the activation/phosphorylation of intracellular kinase of the receptor (Lemmon and Schlessinger 2010). These include epidermal growth factor (EGF) and platelet derived growth factor (PDGF), which regulate a diverse set of cellular responses including proliferation and differentiation (Heldin and Westermark 1999, Wells 1999). The extracellular signals from the receptor are propagated by proteins such as protein kinases. Kinases are enzymes that catalyse the transfer of phosphate groups to amino acids with a free hydroxyl group. There are three types of kinases families depending of the amino acids that are phosphorylated (Dhanasekaran and Premkumar Reddy 1998):

• Serine/threonine kinases
• Tyrosine kinases
• Dual kinases: phosphorylate all three amino acid

Phosphorylation is only one example of a protein post-translational modification (PTM) that are induced by extracellular signals and allow proteins in a signalling pathway to transduce signals. For example, AKT the Ser/Thr kinase is phosphorylated on the Ser473 site and results in its activation (Sarbassov et al. 2005).

Intracellular signalling frequently abides by the writer, reader and eraser toolkit system resulting in the regulation of cell signalling pathways. The writer is the kinase, the reader is the adapter proteins binding phosphotyrosine to propagate cell signals, and the eraser is the phosphatase to ablate the signalling response (Lim and Pawson 2010).Adapter proteins contain specific binding domains to facilitate the propagation of a signalling pathway by increasing the binding partner complex but adapter proteins lack enzymatic activity (Flynn 2001). One such adapter protein is the growth factor receptor-bound protein 2 (GRB2) which recruits molecules to receptor tyrosine kinases (Giubellino et al. 2008). GRB2 contains a Src homology 2 (SH2) domain allowing it to bind to phosphorylated tyrosine kinase receptors (EGFR) and two SRC Homology 3 Domains (SH3) that facilitate binding to son of sevenless (SOS) via proline rich domains. The activation of EGFR brings SOS into close proximity with Ras via GRB2 interaction and this results in an activation of MAPK pathway signalling (Tari and Lopez-Berestein 2001). 

Phosphatases regulate signalling pathways by dampening the signal from an activated pathway. Phosphatases catalyse the dephosphorylation of Ser/Thr and tyr residues thus modulating the activity of protein kinases (Barford 1996). One example is protein tyrosine phosphatases (PTPs); they catalyse the dephosphorylation of tyrosine. PTP was demonstrated to dephosphorylate EGFR, therefore inhibiting the EGFR signalling (Tiganis 2002). Protein phosphorylation can inhibit the activity of kinases, such as the kinase Src tyrosine kinase family that play an important role in cell differentiation, proliferation and cell survival. The phosphorylation of Src on Tyr527 inactivates Src and the dephosphorylation of this site by PTP1B plays a role in the activation of Src (Bouaziz et al. 2007).