FGF signaling regulates salivary gland branching morphogenesis by modulating cell adhesion

Abstract

Loss of FGF signaling leads to defects in salivary gland branching, but the mechanisms underlying this phenotype remain largely unknown. We disrupted expression of Fgfr1 and Fgfr2 in salivary gland epithelial cells and find that both receptors function coordinately in regulating branching. Strikingly, branching morphogenesis in double knockouts is restored by Fgfr1/2 knock-in alleles incapable of engaging canonical RTK signaling, suggesting that additional FGF dependent mechanisms play a role during salivary gland branching. Fgfr1/2 conditional null mutants showed defective cell-cell and cell-matrix adhesion, both of which have been shown to play instructive roles in salivary gland branching. Loss of FGF signaling led to disordered cell-basement membrane interactions in vivo as well as in organ culture. This was partially restored upon introducing Fgfr1/2 wild type or signaling alleles incapable of eliciting canonical intracellular signaling. Together, our results identify non-canonical FGF signaling mechanisms that regulate branching morphogenesis through cell adhesion processes.

Receptor tyrosine kinases: biological functions and anticancer targeted therapy

“…The first tyrosine kinase fusion to be identified was BCR-ABL. This fusion resulted from the translocation t (9,22), also known as the "Philadelphia chromosome". It involved the joining of the ABL1 tyrosine kinase genes on chromosome 9 with the BCR gene on chromosome 22, creating the BCR-ABL fusion oncoprotein.…”

“…RTKs control important functions in tissue homeostasis, cell function, and mammalian development. These functions include tissue repair and regeneration, organ morphogenesis, cell proliferation and survival, and neovascularization 7–11 . Therefore, gaining a deeper understanding of RTKs can help identify potential targets for cancer detection and therapy.…”

“…These functions include tissue repair and regeneration, organ morphogenesis, cell proliferation and survival, and neovascularization. [7][8][9][10][11] Therefore, gaining a deeper understanding of RTKs can help identify potential targets for cancer detection and therapy. This review focuses on the classification and structure of RTKs, the mechanisms of normal and oncogenic activation, their expression in high-incidence tumors, and the different types of targeted drugs.…”

DiverseFgfr1signaling pathways and endocytic trafficking regulate early mesoderm development

“…This raises the question of what functionality remains in the FCPG alleles and how these functions are engaged outside of canonical FGF signaling. Our previous results indicated that while FGFR1/2 regulate cell-matrix and cell-cell adhesion, these processes were not affected in Fgfr1 FCPG or Fgfr2 FCPG homozygous embryos (Ray et al, 2020;Ray and Soriano, 2023). Evidence suggests that both FGFR1 and FGFR2 can recruit SRC family kinases (SFKs).…”

FRS2-independent GRB2 interaction with FGFR2 is not required for embryonic development

“…Homozygous Fgfr1 FCPG/FCPG embryos develop until at least E10.5, while Fgfr2 FCPG/FCPG mice are viable. The large disparity between the FCPG and null alleles for both receptors indicates that partial functionality remains in both the Fgfr1 FCPG and Fgfr2 FCPG alleles (Brewer et al, 2015; Ray et al, 2020; Ray and Soriano, 2023).…”