CBL ubiquitinates FRS2 and FGFR1

Grb2 bound to tyrosine phosphorylated FRS2 forms a ternary complex with Cbl through the binding of the SH3 domains of Grb2 to a proline rich region in Cbl. Grb2-mediated recruitment of Cbl results in ubiquitination of FGFR and FRS2. Cbl is a multidomain protein that posses an intrinsic ubiquitin ligase activity and also functions as a platform for recruitment of a variety of signaling proteins. Multiple mechanisms appear to be required for downregulation of FGFR, as internalization of the receptor is reduced but not abolished if recruitment of CBL to FRS2 is compromised by mutation of GRB2-binding sites.

Grb2与酪氨酸磷酸化的FRS2结合，通过Grb2的SH3结构域与Cbl中富含脯氨酸的区域结合，形成与Cbl的共价三聚体。Grb2介导的Cbl募集导致FGFR和FRS2的泛素化。Cbl作为一种多结构域蛋白，具有内在的泛素连接酶活性，并充当多种信号蛋白募集的平台。对于FGFR的下调，似乎需要多种机制，因为即使CBL对FRS2的募集因GRB2结合位点的突变而受损，受体的内化也仅减少而非完全消失。