Novel regulatory mechanism for intercellular communication identified

Neighboring cells in tissues are able to communicate directly with each other by exchanging ions and signaling molecules through intercellular channels. These channels are assembled into specialized intercellular plasma membrane domains called gap junctions. Cell-cell communication via gap junctions plays an important role in cell growth control and differentiation. Gap junctions are frequently deregulated in cancer cells, and there is significant evidence that loss of gap junction function is an important event in carcinogenesis.

Gap junction channels consist of transmembrane proteins called connexins, of which the prototype member is Connexin43. Previous studies in Edgar Rivedal’s group have shown that Connexin43 is post-translationally modified by ubiquitin. However, the role of this modification in regulation of Connexin43 has remained unknown. The recently published study provides new insights into the role of ubiquitin in degradation of Connexin43. The authors found that activation of the mitogen-activated protein (MAP) kinase pathway results in recruitment of ubiquitin to gap junction plaques, followed by internalization and trafficking of ubiquitinated Connexin43 to early endosomes. The study identifies a critical role of the two ubiquitin-binding proteins Hrs and Tsg101 in mediating lysosomal degradation of Connexin43 and in modulating the level of intercellular communication via gap junctions.

These findings could have important implications for understanding the molecular mechanisms underlying the deregulation of Connexin43 in cancer and other diseases.

Links:
Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101.
Leithe E, Kjenseth A, Sirnes S, Stenmark H, Brech A, Rivedal E.
J. Cell Sci. 2009 Nov 1;122:3883-93. Epub 2009 Oct 6.

Edward Leithe’s project group - cell signaling

Molecular cell biology group