IBYME   02675
INSTITUTO DE BIOLOGIA Y MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Galectin-1 (Gal1) co-opts VEGFR2 (KDR) signaling pathways through the formation of lectin-glycan lattices on highly branched complex N-glycans
Autor/es:
CROCI, DIEGO O.; SALATINO, MARIANA; ILARREGUI, JUAN M.; DOMAICA, CAROLINA;. CERLIANI, JUAN P.; MASCANFRONI, IVÁN; DERGAN-DYLON, SEBASTIÁN; STUPIRSKI, JUAN C , TOSCANO, MARTA A.; AND RABINOVICH, GABRIEL A.
Lugar:
Buenos Aires
Reunión:
Congreso; FAIC; 2010
Resumen:
In previous studies we demonstrated
that galectin-1 (Gal1) links tumor hypoxia and VEGF-mediated angiogenesis. The
present study was conducted to investigate signaling
pathways associated with this pro-angiogenic function and to identify potential
glyco-receptors mediating these effects. We first examined the glycosylation
signature of ECs in resting conditions or exposed to proliferative, tolerogenic
or inflammatory stimuli. In contrast to ECs stimulated with pro-inflammatory (TNF),
TH1-(IFN-g) or TH-17(IL-17)
stimuli, ECs exposed to tolerogenic (IL-10 or TGF-b1) or proliferative (bFGF) signals exhibited a
substantial up-regulation of cell surface N- glycans that are critical for
galectin-1 signaling, an effect which was consistent with galectin-1 binding to
ECs (p<0.01). Screening of the phosphorylation status of a spectrum of
growth factor receptors using signaling arrays revealed a 2-fold increase in
phosphorylation of KDR, Akt and Erk1/2
upon exposure to Gal1, a pattern comparable to that induced by VEGF. Pharmacological
inhibition of Akt or Erk1/2 signaling abrogated Gal1-induced EC proliferation
(p<0.01), migration (p<0.01) and angiogenesis (p<0.05). siRNA-mediated
silencing of KDR completely prevented Akt and ERK1/2 phosphorylation induced by
either Gal1 or VEGF-A. Interruption of N-acetylglucosaminyltransferase V (GnT5)-mediated
N-glycan branching prevented Gal1 but not VEGF-A signaling. Co-immunoprecipitation
revealed specific association of Gal1 with KDR through N-glycan-dependent
interactions. Consistently, KDR blockade or interruption of N-glycan elongation
prevented Gal1-induced EC migration (p<0.01) and morphogenesis (p<0.05),
whereas blockade of VEGFR1, VEGFR3, NRP-1 or VEGF-A had no effect.
Collectively, our results suggest that signaling complexes established between lectins
and specific glycans might serve as alternative or compensatory pathways by
mimicking cognate ligands, thus preserving critical cellular processes such
as angiogenesis.