Chemokines are a family of small cytokines, secreted in response to a variety of signalling proteins. The major role of chemokines is to act as a chemoattractant to guide the migration of cells. However, chemokines must bind to their corresponding receptors to exert their biological activity. Over 45 different chemokines and 23 different chemokine receptors have been identified to date and interactions between them are highly promiscuous, often with one receptors binding to multiple chemokines and some chemokines binding to more than one receptor. This is termed as functional selectivity or biased agonism.

Biased signalling at chemokine receptor 2 (CCR2) has been verified by our collaborators with cell-based assays, when investigating the signalling pathways of CCR2 activated by monocyte chemoattractant protein chemokines (MCP) -1, -2, and -3 in a simple cellular model (HEK293 cells expressing CCR2). Concentration-response curves for different chemokines revealed that while MCP-1 and MCP-3 have similar potencies in a Ca²⁺ mobilisation assay, MCP-3 is ~10-fold more potent in an ERK phosphorylation assay compared to MCP-1. In contrast, MCP-1 and MCP-2 have similar potencies in the ERK phosphorylation assay but MCP-2 is ~10-fold less potent in the Ca²⁺ mobilisation assay.

Phosphorylation patterns induced by different chemokines are the most promising area to elucidate biased signalling networks of chemokines and chemokine receptors, because almost all GPCRs are regulated by phosphorylation and also phosphorylation and dephosphorylation of proteins are essential for cellular signalling processing especially for early signalling. Mass spectrometry-based proteomics and phosphoproteomics studies will help us to understand the mechanism of differential effects of MCP chemokines on the chemokine receptors 2.