Abstract
The 50 amino acid form of TGF-α is cleaved from a conserved integral membrane glycoprotein by a protease that, in many tumor cells, appears to be limiting. To test whether the membrane-bound precursor has biological activity in the absence of processing, we introduced amino acid substitutions at the proteolytic cleavage sites. BHK cells transfected with expression vectors containing these altered sequences do not secrete detectable levels of mature TGF-α into the medium, but express high levels of proTGF-α at the cell surface. Coincubation of these BHK cells with A431 cells demonstrates that membrane-bound proTGF-α may bind to EGF receptors on the surface of contiguous cells, induce receptor autophosphorylation, and thereby produce a rapid rise in A431 intracellular calcium levels. Thus, proTGF-α can be biologically active in the absence of processing, a fact that may have implications for the integral membrane precursors of related growth factors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 495-506 |
| Number of pages | 12 |
| Journal | Cell |
| Volume | 56 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 10 1989 |
Bibliographical note
Funding Information:The authors gratefully acknowledge Noreen Luetteke, Larry Gentry, Diana Gilligan, and Andy Blasband for helpful discussions. We also thank Larry Gentry and Jeffrey Kudlow for generously providing antibodies, Govind Gawdi for carrying out the video image microscopy, Ed C’Keefe for reading the manuscript, and Angie Boudwin for assistance in preparing the manuscript. This work was supported by U.S. Public Health Service grants CA43793 (D. C. L.), DK30002 and DK31683 (H. S. E.), and AGO7218 (8. H.), and by grant CD-209C from the American Cancer Society (J. M.). B. H. was also supported by AHA861299. D. C. L. is a Junior Faculty awardee of the American Cancer Society. B. K. McC. was supported by NRSA award GM12533.