Structural basis of hepatocyte growth factor/scatter factor and MET signalling

Gherardi, Ermanno; Sandin, Sara; Petoukhov, Maxim V.; Finch, J.T.; Youles, Mark; Öfverstedt, Lars-Göran; Miguel, Ricardo Núñez; Blundell, Tom L.; Woude, George F. Vande; Skoglund, Ulf; Svergun, Dmitri I.

doi:10.1073/pnas.0509040103

Cited by 199 publications

(206 citation statements)

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“…Furthermore, these NK2 mutants activate Met through the same conserved mechanism of the NK1-NK1 dimer interface, as the Y124A mutation also abolishes the ability of these NK2 mutants to activate Met. The NK1-NK1 dimer interface has been shown to be required for Met activation by NK1 or by the full-length HGF (7,8,20). Our results here with NK2 further highlight the importance of the NK1-NK1 dimer interface in activation of the Met receptor.…”

Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 99%

“…A synthetic version of the HGF α-chain containing the N-terminal domain and four kringle domains (NK4) has been explored as a HGF antagonist for anticancer therapy (12)(13)(14)(15). Full-length HGF antagonists can also be generated by mutating arginine-494 to glutamate, which makes a noncleavable proHGF, or by mutations in the "activation pocket" of the HGF β-chain (7,16).…”

mentioning

confidence: 99%

“…The sema domain of Met is necessary and sufficient for binding and activation of the receptor by HGF (6). It is believed that HGF induced Met activation is mediated through a formation of a 2∶2 complex where Met dimerization is primarily mediated by dimer formation of HGF (7,8).HGF is a disulfide-linked two chain protein of 728 amino acids with its α-chain containing an N-terminal domain and four kringle domains, and its β chain containing a serine protease domain. HGF belongs to the family of serine protease growth factors, and is most similar to plasminogen and macrophage stimulating factor (MSP), which is the ligand for RON, a receptor closely related to Met.…”

mentioning

confidence: 99%

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Structural basis for agonism and antagonism of hepatocyte growth factor

Tolbert¹,

Daugherty-Holtrop²,

Gherardi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Hepatocyte growth factor (HGF) is an activating ligand of the Met receptor tyrosine kinase, whose activity is essential for normal tissue development and organ regeneration but abnormal activation of Met has been implicated in growth, invasion, and metastasis of many types of solid tumors. HGF has two natural splice variants, NK1 and NK2, which contain the N-terminal domain (N) and the first kringle (K1) or the first two kringle domains of HGF. NK1, which is a Met agonist, forms a head-to-tail dimer complex in crystal structures and mutations in the NK1 dimer interface convert NK1 to a Met antagonist. In contrast, NK2 is a Met antagonist, capable of inhibiting HGF's activity in cell proliferation without clear mechanism. Here we report the crystal structure of NK2, which forms a "closed" monomeric conformation through interdomain interactions between the N-domain and the second kringle domain (K2). Mutations that were designed to open up the NK2 closed conformation by disrupting the N/K2 interface convert NK2 from a Met antagonist to an agonist. Remarkably, this mutated NK2 agonist can be converted back to an antagonist by a mutation that disrupts the NK1/NK1 dimer interface. These results reveal the molecular determinants that regulate the agonist/antagonist properties of HGF NK2 and provide critical insights into the dimerization mechanism that regulates the Met receptor activation by HGF.cancer metastasis | crystal structure | HGF agonist | HGF antagonist | Met receptor tyrosine kinase H epatocyte growth factor (HGF) and the Met tyrosine kinase receptor form a unique ligand-receptor signaling system where HGF is the only known endogenous ligand that activates Met. HGF is also known as a scattering factor, and its signaling through Met activation is involved in promoting cell proliferation, survival, migration, and branching in a variety of cell types with important roles in angiogenesis, wound repair, and cell migration during development (1, 2). Inappropriate expression of Met or HGF has been implicated in many cancers and is associated with an aggressive phenotype and poor prognosis (1, 3) (www.vai.org/met). Thus, inhibition of Met activity, either by small molecule kinase inhibitors or by protein-based HGF antagonists, has become an important and rational strategy for developing anticancer therapeutics.The Met extracellular domain (ECD), which encompasses approximately 900 amino acids (25-932), is cleaved into α and β chains by the furin protease between residues 307 and 308. The first 519 amino acids of Met form a 7-bladed β-propeller domain, called sema domain, with homology to the semaphorin and plexin protein families (4, 5). Following the sema domain are a cysteine-rich domain and four immunoglobulin-like domains. The sema domain of Met is necessary and sufficient for binding and activation of the receptor by HGF (6). It is believed that HGF induced Met activation is mediated through a formation of a 2∶2 complex where Met dimerization is primarily mediated by dimer formation of HGF (7,8).HGF is a disu...

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Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Structural basis for agonism and antagonism of hepatocyte growth factor

Tolbert¹,

Daugherty-Holtrop²,

Gherardi

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Hepatocyte growth factor/scatter factor (HGF/SF) is a potent angiogenic agent (10), signaling through the Met receptor and downstream MAPK and the PI3K pathways (11)(12). Interestingly, the Met receptor is upregulated during hypoxia, suggesting that the ischemic tissue will be primed for activation by HGF/SF (13).…”

mentioning

confidence: 99%

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

Roy

Soni

Harfouche

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Therapeutic angiogenesis is an emerging paradigm for the management of ischemic pathologies. Proangiogenic Therapy is limited, however, by the current inability to deliver angiogenic factors in a sustained manner at the site of pathology. In this study, we investigated a unique nonglycosylated active fragment of hepatocyte growth factor/scatter factor, 1K1, which acts as a potent angiogenic agent in vitro and in a zebrafish embryo and a murine matrigel implant model. Furthermore, we demonstrate that nanoformulating 1K1 for sustained release temporally alters downstream signaling through the mitogen activated protein kinase pathway, and amplifies the angiogenic outcome. Merging protein engineering and nanotechnology offers exciting possibilities for the treatment of ischemic disease, and furthermore allows the selective targeting of downstream signaling pathways, which translates into discrete phenotypes.N eovascularization in the adult holds the potential for ameliorating ischemic disease, which is the leading cause of morbidity and mortality in the United States (1). Ferrara and Kerbel recently articulated that "therapeutic angiogenesis" is an emerging and exciting frontier of cardiovascular medicine (2). However, while early preclinical studies and phase I clinical trials exhibited promising results with recombinant proteins or gene therapy, more rigorous phase II and III studies have reported conflicting outcomes (3-6). A recent review of these clinical trials highlighted vector "washout" leading to inadequate duration of exposure to the angiogenic agent as a key factor that may have impaired the effectiveness of therapy (7). Indeed, it is now established that sustained activation of downstream signal pathways promotes cellular processes critical for angiogenesis (8). We rationalized that harnessing a nanotechnology-based approach can enable a temporal control over the presentation of the angiogenic factors to the cellular target, thereby altering the activation of downstream signal transduction.While nanoformulation of angiogenic proteins is an attractive strategy, the synthesis and instability of these large complex glycosylated structures pose a significant barrier (9). Hepatocyte growth factor/scatter factor (HGF/SF) is a potent angiogenic agent (10), signaling through the Met receptor and downstream MAPK and the PI3K pathways (11-12). Interestingly, the Met receptor is upregulated during hypoxia, suggesting that the ischemic tissue will be primed for activation by HGF/SF (13). These results indicate that HGF/SF could emerge as an attractive therapy for angiogenesis. However, HGF/SF is a heparin-binding protein with a complex multidomain structure consisting of an N-terminal (N) domain, four copies of the kringle domain (K1 to K4) and a C-terminal domain homologous to that of serine proteineases (SP) (Fig. 1A) (14). Biologically active HGF/SF is produced by proteolytic cleavage of the linker connecting the fourth kringle and the SP domain yielding a two-chain (α/β)-heterodimer, in which both the α-and the...

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Calculation of Real Space Parameters and Ab Initio Models from Isotropic Elastic SANS Patterns

Konarev¹,

Svergun²

2011

Neutrons in Soft Matter

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Structural basis of hepatocyte growth factor/scatter factor and MET signalling

Cited by 199 publications

References 46 publications

Structural basis for agonism and antagonism of hepatocyte growth factor

Structural basis for agonism and antagonism of hepatocyte growth factor

Coupling growth-factor engineering with nanotechnology for therapeutic angiogenesis

Calculation of Real Space Parameters and Ab Initio Models from Isotropic Elastic SANS Patterns

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