Pseudo-active sites of protease domains: HGF/Met and Sonic hedgehog signaling in cancer.
Proteases represent a large class of enzymes with crucial biological functions. Although targeting various relevant proteases for therapeutic intervention has been widely investigated, structurally related proteins lacking proteolytic activity (pseudo-proteases) have received relatively little attention. Two distinct clinically relevant cancer pathways that contain signaling proteins with pseudo-protease domains include the Met and Hedgehog (Hh) pathways. The receptor tyrosine kinase Met pathway is driven by hepatocyte growth factor (HGF), a plasminogen-related ligand that binds Met and activates intracellular pathways resulting in cell proliferation, angiogenesis, motility and survival. HGF is a disulfide-linked alpha/beta-heterodimer having a trypsin serine protease-like beta-chain. The Hh pathway is driven by Sonic hedgehog (Shh), which has a Zn(2+) metalloprotease fold and binds Patched1 (Ptc1), which de-represses Smoothened and ultimately activates Gli-dependent transcription. Although HGF and Shh differ in structure and function, the pseudo-catalytic sites of both HGF and Shh are crucial for signal transduction. For HGF, this region binds the Met beta-propeller domain, which leads to Met dimerization and signaling. For Hh, this region binds to the antagonist receptor Hedgehog-interacting protein (Hhip) and most probably to Ptc1 as well. Thus, for both HGF and Hh pathways, targeting ligand pseudo-active sites represents a new strategy for regulation.
Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
Henry R
HR
Maun
Daniel
D
Kirchhofer
Robert A
RA
Lazarus
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D020134:Catalytic Domain; D015195:Drug Design; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D045726:Metalloproteases / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D054730:Protein Interaction Domains and Motifs; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D057057:Serine Proteases / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
D002352:Carrier Proteins; C066855:HGF protein, human; C117596:HHIP protein, human; D053823:Hedgehog Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D017978:Receptors, Growth Factor; C509239:SHH protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D045726:Metalloproteases; D057057:Serine Proteases