Mechanisms of other ligands and its receptor as positive modulators of (ErBb) family signaling activation in cholangiocarcinoma. Other ligands and receptors as positive modulators contribute to the activation of the ErBb family via several mechanisms to activate ErBbs signaling in the progression of cholangiocarcinoma (CC). Interleukin (IL)-6, mucins, and neurotensin (NTS)/NTS receptors-mediated EGFR and ERBB2 overexpression leading to activation of (ErBb) family signaling. EGFR also can be activated by interaction with other receptors and angiotensin II (Ang II) mediated activation of G protein-coupled receptor (GPCR) lead to the transactivation of EGFR via cross-talk between GPCR and EGFR. PGE2: Prostaglandin, IGF: Insulin-like growth factor, IGF1R: Insulin-like growth factor-1 receptor, MMPs: Matrix metallopeptidases, CREB: Cyclic AMP response element-binding protein, PDGFR: Platelet-derived growth factor, L1CAM: L1 cell adhesion molecule, NRP1: Neuropilin-1, MUC: mucin, TIMP1: TIMP metallopeptidase inhibitor 1, Ang II: Angiotensin II, AT1R: Angiotensin receptor, NTS: Neurotensin, NTSR: NTS receptor.