Motogenic and morphogenic activity of epithelial receptor tyrosine kinases.

Abstract

Abstract. Receptor tyrosine kinases play essential roles in morphogenesis and differentiation of epithelia. Here we examined various tyrosine kinase receptors, which are preferentially expressed in epithelia (c-met, c-ros, c-neu, and the keratin growth factor [KGF] receptor), for their capacity to induce cell motility and branching morphogenesis of epithelial cells. We exchanged the ligand-binding domain of these receptors by the ectodomain of trkA and could thus control signaling by the new ligand, NGF. We demonstrate here that the tyrosine kinases of c-met, c-ros, c-neu, the KGF receptor, and trkA, but not the insulin receptor, induced scattering and increased motility of kidney epithelial cells in tissue culture. Mutational analysis suggests that SHC binding is essential for scattering and increased cell motility induced by trkA. The induction of motility in epithelial cells is thus an important feature of various receptor tyrosine kinases, which in vivo play a role in embryogenesis and metastasis. In contrast, only the c-met receptor promoted branching morphogenesis of kidney epithelial ceils in three-dimensional matrices, which resemble the formation of tubular epithelia in development. Interestingly, the ability of c-met to induce morphogenesis could be transferred to trkA, when in a novel receptor hybrid COOH-terminal sequences of c-met (including Y14 to Y16) were fused to the trkA kinase domain. These data demonstrate that tubulogenesis of epithelia is a restricted activity of tyrosine kinases, as yet only demonstrated for the c-met receptor. We predict the existence of specific substrates that mediate this morphogenesis signal.

Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor

“…In a similar manner to HGF-induced EMT, (Royal and Park, 1995;Potempa and Ridley, 1998;Royal et al, 2000), we show that activated ErbB-2/Neu promotes epithelial cell dispersal. This supports observations that a chimeric Trk-ErbB-2 receptor can induce partial dispersal of MDCK cells, although these cells were not analysed in detail (Sachs et al, 1996). By indirect immuno¯uorescence, cells expressing activated ErbB-2/Neu NT show loss of cortical actin and the formation of bundled actin stress ®bers, as well as loss of peripheral vinculin-containing focal complexes and the appearance of large intracellular focal contacts (Figure 3).…”

“…To date Met was the only receptor capable of inducing a branching tubulogenic program in MDCK cells, and previous studies using a chimeric Trk-ErbB2 receptor failed to induce tubulogenesis in response to stimulation (Sachs et al, 1996). This may re¯ect the Figure 5 and Maroun et al, 1999).…”

“…Immunoprecipitation of Shc and immunoblotting with antiphosphotyrosine sera, shows an increase in Shc phosphorylation predominantly in NT, YD and YEexpressing cells and to a lesser extent in YC-expressing cells (Figure 7). Previous data have suggested that when compared with other receptor tyrosine kinases only the Met receptor promotes tubulogenesis of MDCK cells in collagen (Sachs et al, 1996;Maroun et al, 1999). To establish whether NT-induced scatter and tubulogenesis of MDCK cells is mediated through an enhancement of Met activation by an activated Neu receptor, we have examined Met phosphorylation.…”

Differential regulation of Shc adaptor proteins in skeletal muscle, spinal cord and forebrain of aged rats with sensorimotor impairment

“…The knock-out experiments by Pawson and colleagues (Sakai et al ., 2000;Lai & Pawson, 2000) elucidated that ShcA is nonredundant for a normal development of the heart and vasculature, probably acting by increasing the cellular sensitivity to small amounts of growth factors. ShcA appears also to be important for cytoskeletal adaptations in growing cells (see also Sachs et al ., 1996). In contrast, animals deficient in ShcB and/or ShcC exhibit changes in the development of the nervous system (Sakai et al ., 2000).…”

Hepatocyte growth factor/c-metsignaling pathway is required for efficient liver regeneration and repair

“…The receptor encoded by the c-met gene is a disulfide linked ␣͞␤ heterodimer that is generated by proteolytic processing of a single polypeptide precursor (7). It has been demonstrated that the activation of the multiple signal transduction pathways downstream of c-met takes place via the multidocking site, a short sequence motif near the C terminus of the ␤ chain (8). Furthermore, the two tyrosine residues (Tyr-1349 and Tyr-1356) located within the multidocking site have been shown to be of crucial importance in recruiting several signal transducer and adaptor molecules that act downstream of c-met (8 -10).…”