Figure 6.

CXCR4 and PaCIC survival and motility. (A) CXCR4 is a G-protein coupled receptor (GPCR) that in PaCa is mostly recovered in association with CD44v6 and/or Tspan8. Activation is initiated by binding of its ligand SDF1. Signals are transferred via the G protein subunits, which promote Ca2+ influx, and either via MAPK or Rho chemotaxis and migration. Chemotaxis and proliferation can also proceed via the Gα, Ras, Raf, pERK1,2 activation route. Activation of PI3K/Akt, Bcl2/pBAD promotes proliferation and survival. The latter is also supported by activation of the STAT-Jak pathway. PI3K/Akt can also initiate activation of transcription factors. Independent of the trimeric G-protein complex, CXCR4 associates with GRK, arrestin and clathrin. The complex becomes internalized, which is accompanied by reduced proliferation and survival. (B) Activation of β-catenin, NFκB and CREB supports transcription of CXCR4, SDF1, Smo, SHH, VEGF, MMP, and Bcl2. These genes are important in PSC activation, recruitment of immunosuppressive MDSC and Treg and the shift of M1 to M2 and in supporting angiogenesis, which may not be dominating in PaCa. Full name of proteins are listed in Table S1. It should be noted that the dominant activity of CXCR4 in promoting chemotaxis and motility covers only one, not essentially dominating feature in PaCIC.