Peripheral nerve development involves a symbiotic and dynamic interaction between axons and Schwann cells (1). When Schwann cell precursors first contact axons, they are actively dividing, flat, GAP43-positive cells. Their subsequent differentiation into committed Schwann cells, which in the rat occurs around embryonic days 16 and 17, is marked by the acquisition of a bipolar morphology and S100 immunoreactivity (2). At this stage, migrating cells extend processes, which penetrate between axons and segregate them into progressively smaller bundles. Schwann cell proliferation and segregation continue such that in the early neonate, each myelinated axon is wrapped by a single myelinating Schwann cell. Withdrawal from the cell cycle at postnatal days 2-4 (3) initiates terminal Schwann cell differentiation and the onset of myelination of a subset of large-diameter axons.

We describe a mechanism connecting the adaptive behavior of the bacterial mechanosensitive channel MscS to the flexibility of the pore-lining helix TM3. Simulated expansion of the channel structure revealed straightening of a characteristic kink near Gly113 in the open state; return to the closed state produced an alternative kink at Gly121. Patch-clamp experiments showed that higher helical propensity introduced by a G113A mutation prevented inactivation. A similar mutation, G121A, kinetically impeded both closure and inactivation. Duplicating the glycines at each of these sites to increase flexibility produced directly opposite effects. The severely toxic G113A G121A mutation resulted in channels that could not inactivate or close with the release of tension. These data suggest that the open MscS features straight TM3 helices, which act as collapsible 'struts'. Closure and desensitization rely on buckling at Gly121, whereas the crystal-like kink at Gly113 is a feature of the inactivated state.

Members of the epidermal growth factor receptor (EGFR) subfamily of receptor protein tyrosine kinases have been implicated in the pathogenesis of various malignancies. The ability of one EGFR subfamily member to influence, or function synergistically with, another is likely to be a general feature of these receptors. To assess the role of receptor heterodimerization, we analyzed the ability of Neu differentiation factor (NDF) to induce cell growth and transformation of NIH 3T3 cells transfected with different combinations of the EGFR subfamily of receptors. NDF induced mitogenesis, but not transformation, of cells expressing either HER3 or HER4 alone. However, NDF-induced cell transformation was observed when either HER1 or HER2 was coexpressed with HER3 or HER4. In analogous receptor phosphorylation experiments, NDF-induced transphosphorylation appears to be correlated with synergistic transformation of NIH 3T3 cells. Interestingly, transphosphorylation between HER1 and HER4 can be stimulated by either EGF or NDF.

The Neu/HER‐2 receptor tyrosine kinase is overexpressed in some types of human adenocarcinomas, including tumors of the breast and the ovary. A 44 kDa glycoprotein that elevates tyrosine phosphorylation of Neu has been isolated and named Neu differentiation factor (NDF), or heregulin. Here we show that NDF affects tyrosine phosphorylation of Neu in human tumor cells of breast, colon and neuronal origin, but not in ovarian cells that overexpress the receptor. By using monoclonal antibodies (mAbs) to Neu, we found that the ovarian receptor is immunologically and biochemically similar to the mammary p185neu. Nevertheless, unlike breast‐derived Neu, the ovarian protein did not display covalent cross‐linking to radiolabeled NDF, and was devoid of ligand‐induced association with phosphatidylinositol 3′‐kinase. Direct binding analysis showed that NDF binds with high affinity (Kd approximately 10(−9) M) to mammary cells, but its weak association with ovarian cells is probably mediated by heparin‐like molecules. Similar to the endogenous receptor, the ectopically overexpressed Neu of mammary cells, but not of ovarian and fibroblastic cells, exhibited elevated levels of NDF‐induced phosphorylation and covalent cross‐linking of the radiolabeled factor. Taken together, our results imply that NDF binding to cells requires both Neu and an additional cellular component, whose identity is still unknown, but its tissue distribution is more restricted than the expression of the neu gene.

Neu differentiation factor (NDF, also cafled