Signal Processing

Specificity, duration and strength of ErbB-mediated intracellular signals are controlled by the ligand type, the composition of the receptor-dimer, as well as by the available spectrum of intracellular docking molecules that associate with specific phosphotyrosine residues on the cytoplasmic tail of an ErbB molecule. Which sites are phosphorylated, and hence which docking molecules are recruited to the receptors, is determined by the ligand and by the receptor heterodimer. Among the signaling cascades that are stimulated upon activation of ErbB receptors are MAPK, PI3 K, PLCy, protein kinase C, and the Jak-STAT pathway. The Ras- and Shc-mediated activation of the MAPK pathway is common to all ErbB ligands, and the PI3K-activated Akt pathway is activated by most of the ErbBs. In addition, each receptor employs a specific set of signaling molecules: ErbB3 cannot bind c-Cbl, Grb2, PLCy, or GAP, but can associate with Shc and Grb7. Within the nucleus such signaling events initiate transcriptional programs involving transcription factors like fos, Jun, and Myc, Sp1, Forkhead, as well as Ets family transcription factors (Yarden and Sliwkowski 2001). ErbB signals are turned off by mechanisms that depend on the receptor type and the composition of the receptor dimer. ErbB1 is the only receptor that is primarily targeted to lysosomal degradation whereas ErbB2, -3 and -4 are endocytosis impaired and are repeatedly recycled back to the cell surface. Moreover, ErbB2 decreases the rate of internalization while increasing the rate of recycling of its partners.

Still, our knowledge is limited about how distinct ErbB-dependent intracellular signaling pathways are able to elicit specific cellular responses, i.e., proliferation, migration, or survival. Very recently Nancy Hynes's group identified a novel intracellular signaling component, MEMO (mediator of ErbB2-driven cell motility), which specifically couples ErbB2 dependent signals to cell motility (Marone et al. 2004). MEMO most probably interacts with a phosphotyrosine at position 1227 through Shc. After ErbB2 activation, MEMO-defective cells fail to extend microtubules toward the cell cortex, indicating that MEMO controls cell migration by directly relaying ErbB2-mediated signals to the cytoskeleton (Marone et al. 2004).

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