The activation of PDGFRs is dependent on the homotypic interactions at the membrane-proximal region of the extracellular segment

(A) Model of PDGFR activation by PDGF-B. The dimeric PDGF ligand binds the D2–D3 boundary of PDGFRs, enabling or forcing the interaction between PDGFR D4 domains. The precise positioning of D4–D5 domains leads to transmembrane and juxtamembrane changes, ultimately leading to the activations of the tyrosine kinase domain. (B) The PDGFR D4–D4 homotypic interaction is likely analogous to the KIT D4–D4 interaction. Shown is the part of the structure of stem cells factor (SCF) in complex with KIT D1–D5. The D4 domains from two copies of receptors are colored in orange and pink respectively. The inter-receptor salt bridges are shown as sticks. (C) PDGFR D4–D4 interaction is also likely to be analogous to that of the D7 domains of VEGFRs, the class of RTKs evolutionarily related to PDGFRs. (D) Sequence comparison of the segment that provides inter-domain interactions for PDGFRs, KIT, and VEGFR2.

A: A PDGF receptor-bearing cell that does not produce PDGF itself responds to PDGF via activation of receptors at the cell surface. This initiates activation of intracellular signaling pathways leading to cell growth, proliferation, and survival.

B: In a PDGF receptor-bearing cell that produces PDGF-A or -B, the ligands will meet and activate the receptors already in the ER, Golgi, and secretary vesicles. Whereas some intracellular signaling pathways are activated intracellularly, other pathways important for mitogenesis are not activated until the ligand–receptor complex reaches the cell membrane.

Examination of the different signalling cascades, induced by RTKs, established Ras/mitogen-activated protein kinase (MAPK),PI-3 kinase and phospholipase-γ (PLCγ) pathways as key downstream mediators of the PDGFR signalling.

Дата добавления: 2014-01-14