Neoplastic Transformation Induced by the Gep Oncogenes Involves the Scaffold Protein JNK-interacting Leucine Zipper Protein

Neoplasia. 2011 Apr;13(4):358-64. doi: 10.1593/neo.101622.

Abstract

The activated mutants of the α-subunits of G proteins G(12) and G(13) have been designated as the gep oncogenes owing to their ability to stimulate diverse oncogenic signaling pathways that lead to neoplastic transformation of fibroblast cell lines and tumorigenesis in nude mice models. Studies from our laboratory as well as others have shown that the growth-promoting activities of Gα(12) and Gα(13) involve potent activation of c-Jun N-terminal kinases (JNKs). Our previous studies have indicated that the JNK-interacting leucine zipper protein (JLP), a scaffold protein involved in the structural and functional organization of the JNK/p38 mitogen-activated protein kinase module, tethers Gα(12) and Gα(13) to the JNK signaling module. In the present study, in addition to demonstrating the physical association between JLP and Gα(12), we show that this interaction is enhanced by the receptor- or mutation-mediated activation of Gα(12). We also establish that JLP interacts with Gα(12) through the C-terminal domain that has been previously identified to be involved in binding to Gα(13). Furthermore, using this C-terminal domain as a competitively inhibitor of JLP that can disrupt Gα(12)-JLP interaction, we demonstrate that JLP is required for the stimulation of JNK by Gα(12). Our results also indicate that such JLP interaction is required for Gα(12) as well as Gα(13)-mediated neoplastic transformation of JLP. These studies demonstrate for the first time a functional role for JLP in the gep oncogene-regulated neoplastic signaling pathway.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • COS Cells
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism*
  • Chlorocebus aethiops
  • Enzyme Activation / genetics
  • GTP-Binding Protein alpha Subunits, G12-G13 / genetics*
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • GTP-Binding Protein alpha Subunits, G12-G13 / physiology
  • Mice
  • NIH 3T3 Cells
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Protein Interaction Domains and Motifs / genetics
  • Protein Interaction Mapping
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • Spag9 protein, mouse
  • GTP-Binding Protein alpha Subunits, G12-G13