Research / Clinical Summary

Partho Ghosh, PhD Associate Professor, Chemistry & Biochemistry Cancer Biology Program Contact by Email

A major focus of our laboratory is in understanding how the mammalian receptor tyrosine kinase Met (also called hepatocyte growth factor receptor, HGFR) is activated by InlB (internalin B, 67 kDa), a protein secreted by the facultative intracellular bacterial pathogen Listeria monocytogenes. Similar to other receptor tyrosine kinases, dysfunction of Met is linked to a plethora of malignancies, such as kidney, breast, liver, and gastric carcinomas.

We have previously demonstrated that InlB acts as a functional mimic of hepatocyte growth factor (HGF, 80 kDa), the endogenous ligand of Met. Stimulation of Met by InlB leads to induction of phagocytic uptake of the bacterium by mammalian cells, as well as mitosis and proliferation in mammalian cells. We are studying in detail (using tools of structural biology, biochemistry, genetics, and cell biology) how binding of InlB to Met leads to activation of this receptor.

In contrast to HGF, which is a proteolytically processed glycoprotein containing numerous cysteines, InlB is easily produced in folded form in bacteria and highly manipulable. The great experimental tractability of InlB offers the possibility of making quick strides in understanding the mechanism of Met activation and providing knowledge that may be applicable to cancer therapies.

1. Marino M, Braun L, Cossart P & Ghosh P. (1999) Structure of the InlB leucine rich repeats, a domain that triggers host cell invasion by the bacterial pathogen L. monocytogenes. Molecular Cell 4:1063-1072.

2. Marino M, Banerjee M, Jonquières R, Cossart P & Ghosh P. (2002) GW domains of the L. monocytogenes invasion protein InlB are SH3-like and mediate binding to host ligands. EMBO J. 21:5623-5634.

3. Copp J, Marino M, Banerjee M, Ghosh P & van der Geer P. (2003) Multiple regions of internalin B contribute to its ability to turn on the Ras-MAP kinase pathway. Journal of Biological Chemistry 278 (10):7783-7789.

4. Banerjee M, Copp J, Vuga D, Marino M, Chapman T, van der Geer P & Ghosh P. (2004) GW domains of the L. monocytogenes invasion protein InlB are required for potentiation of Met activation. Molecular Microbiology 52(1):257-271.

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