Utilizing the activation mechanism of serine proteases to engineer hepatocyte growth factor into a Met antagonist

Kirchhofer, Daniel; Lipari, Michael T.; Santell, Lydia; Billeci, Karen L.; Maun, Henry R.; Sandoval, Wendy; Moran, Paul; Ridgway, John Brady; Eigenbrot, Charles; Lazarus, Robert A.

doi:10.1073/pnas.0700184104

Cited by 45 publications

(39 citation statements)

References 40 publications

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“…Taking together these observations we can suggest that local manipulation of JAK-STAT activation can be a very perspective therapeutic approach for managing of cholangiocarcinoma at different stages of its progression. Recent advances in development of hormonal and cytokine antagonists (recombinant proteins for Prl and GH and peptide for IL-6 [145][146][147] ) give us an efficient tool for this treatment. Since synthetic specific inhibitors of JAK and other tyrosine kinases are intensively developed, we could suggest their efficient application for managing of cholangiocarinoma in addition to antagonists.…”

Section: Perspective Therapeutic Addressing Of the Jak-stat Pathwaymentioning

confidence: 99%

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

Smirnova¹

2007

WJG

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The features of JAK-STAT signaling in liver cells are discussed in the current review. The role of this signaling cascade in carcinogenesis is accentuated. The possible involvement of this pathway and alteration of its elements are compared for normal cholangiocytes, cholangiocarcinoma predisposition and development. Prolactin and interleukin-6 are described in detail as the best studied examples. In addition, the non-classical nuclear translocation of cytokine receptors is discussed in terms of its possible implication to cholangiocarcinoma development.

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Section: Perspective Therapeutic Addressing Of the Jak-stat Pathwaymentioning

confidence: 99%

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

Smirnova¹

2007

WJG

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“…It is secreted as an inactive single-chain precursor pro-MSP, which requires proteolytic cleavage at the Ser-Lys-Leu-Arg 483 #Val 484 bond to attain functional activity (5,6). In HGF, cleavage at the corresponding Arg 494 #Val 495 bond results in distinct structural rearrangements within the HGF b-chain and the formation of a MET-binding site that is competent for signal transduction (7)(8)(9). Comparable conformational rearrangements centered at the "pseudo-active site" in the MSP b-chain are likely to occur on activation cleavage of pro-MSP (7).…”

Section: Introductionmentioning

confidence: 99%

Proteolytic Activation of Pro-Macrophage-Stimulating Protein by Hepsin

Ganesan

Kolumam

Lin

et al. 2011

Molecular Cancer Research

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“…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).…”

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confidence: 99%

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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Utilizing the activation mechanism of serine proteases to engineer hepatocyte growth factor into a Met antagonist

Cited by 45 publications

References 40 publications

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

JAK-STAT pathway in carcinogenesis: Is it relevant to cholangiocarcinoma progression?

Proteolytic Activation of Pro-Macrophage-Stimulating Protein by Hepsin

Structural basis for agonism and antagonism of hepatocyte growth factor

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