The internalized receptors are transported to the lysosomes for degradation. Cytosolic complexes such as ESCRTs and their associated proteins are involved in these highly dynamic and regulated processes. Grb2 seems to be involved in these processes as well, since mutations in either of its SH3 domains impede the epidermal growth factor receptor trafficking from the early to the late endosomes and the Masitinib formation of the multivesicular bodies. Interestingly, a similar phenotype was observed when HDPTP levels were knockdown in cell culture. The mechanisms by which Grb2 regulates endocytosis of RTKs is not fully INCB28060 understood, and we can hypothesize that HD-PTP and Grb2 work together, probably with other proteins as well, to assemble and/or coordinate the assembly of endosome-associated protein complexes essential for vesicle biogenesis and protein sorting. GrpL, also known as Gads, Grap2, Mona and Grf40, is expressed only in hematopoietic tissues, including bone marrow, lymph node, and spleen. Both Grb2-family adapters found to bind to HD-PTP are important regulators in lymphocytes signaling and development. T-cell receptor engagement with anti-CD3 antibodies or peptide MHC complexes induces a cascade of Tyr phosphorylations, which leads to the fast recruitment and subsequent activation of downstream effectors of the TCR/CD3 activated complex. Adapter proteins such as LAT become phosphorylated on multiple Tyr residues. Phosphorylation of LAT creates binding sites for SH2 domains of other proteins, including phospholipase C c1, Grb2, GrpL and Grap. Thus, SLP76, which is constitutively bound to GrpL is brought to the TCR signaling complex at the plasma membrane. In addition, Grb2 recruits Sos1 and E3 ubiquitin ligase c- Cbl, which are bound to its SH3 domains. These interactions are crucial for the regulation of calcium signaling in T cells and for coupling the TCR to Ras through a pathway involving PLC-c1, Tec family kinases, and RasGRP. c-Cbl mediates the ubiquitination of TCRf chain leading to TCR internalization into endosomal compartments and subsequent degradation of the receptor in activated T cells. c-Cbl also mediates the segregation of LAT/GrpL/SLP-76- containing microclusters from activated TCR/CD3 complexes and further induces their endocytosis. It is conceivable that these endocytozed microclusters contain other adapters and enzymes associated with activated LAT.