A non-canonical Grb2-PLC-gamma1-Sos cascade triggered by lipovitellin 1, an apolipoprotein B homologue.

The injection of the Grb2 adapter in Xenopus oocytes promotes G2/M transition without stimulation from a receptor only the first day after the oocytes removal from the ovaries. This cell cycle reinitiation is Ras-dependent and requires the SH2 and SH3 domains of Grb2. The SH2 domain of Grb2 binds the tyrosine phosphorylated lipovitellin1, a homologue of the human apolipoprotein B. The N-SH3 domain of Grb2 is linked to a proline-rich sequence of the C2 domain of PLC-gamma1, PLC-gamma1 itself is linked, through its SH3 domain, to the C-terminal proline-rich region of Sos. When Grb2-PLC-gamma1-Sos is associated, PLC-gamma1 is not phosphorylated on Y783 but shows a phospholipase activity. Inhibition of lipovitellin 1 or PLC-gamma1 avoids Grb2-induced cell cycle reinitiation. Therefore, the Grb2-lipovitellin 1 association is the starting point of a novel signaling pathway, where PLC-gamma1 binds Grb2 and recruits Sos.