Advertisement

Ectodomain shedding of TGF‐α and other transmembrane proteins is induced by receptor tyrosine kinase activation and MAP kinase signaling cascades

Huizhou Fan, Rik Derynck

Author Affiliations

  1. Huizhou Fan1 and
  2. Rik Derynck*,1
  1. 1 Departments of Growth and Development, and Anatomy, Programs in Cell Biology and Developmental Biology, University of California at San Francisco, San Francisco, CA, 94143, USA
  1. *Corresponding author. E-mail: derynck{at}itsa.ucsf.edu
View Full Text

Abstract

A variety of transmembrane proteins, such as transforming growth factor‐α (TGF‐α), tumor necrosis factor‐α (TNF‐α) and L‐selectin, undergo shedding, i.e. cleavage of the ectodomain, resulting in release of a soluble protein. Although the physiological relevance of ectodomain shedding is well recognized, little is known about the signaling mechanisms activating this process. We show that growth factor activation of cell surface tyrosine kinase receptors induces ectodomain cleavage of transmembrane TGF‐α through activation of the Erk MAP kinase signaling cascade without the need for new protein synthesis. In addition, expression of constitutively activated MEK1 or its downstream target Erk2 MAP kinase was sufficient to stimulate TGF‐α shedding. The basal cleavage level in the absence of exogenous growth factor stimulation was due to p38 MAP kinase signaling. Accordingly, a constitutively activated MKK6, a p38 activator, activated TGF‐α shedding in the absence of exogenous stimuli. In addition to TGF‐α shedding, these mechanisms also mediate L‐selectin and TNF‐α cleavage. Thus, L‐selectin shedding by neutrophils, induced by N‐formylmethionyl‐leucyl‐phenylalanine, was strongly inhibited by inhibitors of Erk MAP kinase or p38 MAP kinase signaling. Our results indicate that activation of Erk and p38 signaling pathways may represent a general physiological mechanism to induce shedding of a variety of transmembrane proteins.

  • Received August 11, 1999.
  • Revision received October 22, 1999.
  • Accepted October 22, 1999.
View Full Text