Hepatocyte growth factor/scatter factor and its interaction with heparan sulphate and dermatan sulphate

Catlow, Krista; Deakin, Jon A.; Delehedde, Maryse; Fernig, David G.; Gallagher, John T.; Pavão, Mauro S. G.; Lyon, Malcolm

doi:10.1042/bst0310352

Cited by 33 publications

(20 citation statements)

References 6 publications

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“…Importantly, interaction of NK1 with Met depended on the presence of heparin. Addition of heparin increased the NK1-Met binding signal by Ͼ200-fold, consistent with the fact that Met activation by NK1 requires the presence of heparin as a Met coreceptor (8,9,18,19).…”

Section: Direct Binding Of the Human And Mouse Nk1 To The Met Extracementioning

confidence: 63%

A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist

Tolbert¹,

Daugherty²,

Gao

et al. 2007

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

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Hepatocyte growth factor (HGF) activates the Met receptor tyrosine kinase by binding and promoting receptor dimerization. Here we describe a mechanistic basis for designing Met antagonists based on NK1, a natural variant of HGF containing the N-terminal and the first kringle domain. Through detailed biochemical and structural analyses, we demonstrate that both mouse and human NK1 induce Met dimerization via a conserved NK1 dimer interface. Mutations designed to alter the NK1 dimer interface abolish its ability to promote Met dimerization but retain full Met-binding activity. Importantly, these NK1 mutants act as Met antagonists by inhibiting HGF-mediated cell scattering, proliferation, branching, and invasion. The ability to separate the Metbinding activity of NK1 from its Met dimerization activity thus provides a rational basis for designing Met antagonists. This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors.cancer therapy ͉ heparin ͉ hepatocyte growth factor ͉ Met antagonist ͉ tumor metastasis

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Section: Direct Binding Of the Human And Mouse Nk1 To The Met Extracementioning

confidence: 63%

A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist

Tolbert¹,

Daugherty²,

Gao

et al. 2007

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

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“…Indeed, inactive [155] and inhibitory HS structures have been described for some activities [107,146] but, neither binding nor activity depends on sequences and charge alone [107,146], although charge undoubtedly plays an important role bringing the interacting species into proximity [156,157]. However, activity does not depend on the presence of particular 'key sulfates' [158] yet, paradoxically, there is a sizeable and presumably energetically costly biosynthesis apparatus for HS and heparin [159], the regulation of which is currently unclear.…”

Section: Summary Of Findingsmentioning

confidence: 99%

Heparan sulfate and heparin interactions with proteins

Meneghetti

Hughes

Rudd

et al. 2015

J. R. Soc. Interface.

256

241

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Heparan sulfate (HS) polysaccharides are ubiquitous components of the cell surface and extracellular matrix of all multicellular animals, whereas heparin is present within mast cells and can be viewed as a more sulfated, tissuespecific, HS variant. HS and heparin regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro, ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. The properties that have been thought to bestow protein binding and biological activity upon HS and heparin vary from high levels of sequence specificity to a dependence on charge. In contrast to these opposing opinions, we will argue that the evidence supports both a level of redundancy and a degree of selectivity in the structure-activity relationship. The relationship between this apparent redundancy, the multi-dentate nature of heparin and HS polysaccharide chains, their involvement in protein networks and the multiple binding sites on proteins, each possessing different properties, will also be considered. Finally, the role of cations in modulating HS/heparin activity will be reviewed and some of the implications for structure-activity relationships and regulation will be discussed.

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“…Although the bioactivities of many cytokines (e.g., basic growth factor-1, fibroblast growth factor, and hepatocyte growth factor) and chemokines (e.g., platelet factor-4, stromal factor-1, IL-8, neutrophil-activating peptide-2, growth-related oncogene-␣, and RANTES) are regulated by glycosaminoglycans (21)(22)(23)(24)(25)(26)(27)(28), CSF-1 is the only cytokine/growth factor reported to exist as a proteoglycan, and the glycosaminoglycan attachment site consensus sequence of Ser-Gly-X-Gly/Ala in CSF-1 is highly conserved. In addition, the spCSF-1 and sgCSF-1 contribute approximately equally to the total circulating CSF-1, i.e., each generates ϳ50% (14).…”

Section: Acrophage (M)mentioning

confidence: 99%

Distinct In Vivo Roles of Colony-Stimulating Factor-1 Isoforms in Renal Inflammation

Jang

Herber

Jiang

et al. 2006

The Journal of Immunology

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CSF-1, the major regulator of macrophage (Mφ) development, has three biologically active isoforms: a membrane-spanning, cell surface glycoprotein, a secreted glycoprotein, and a secreted proteoglycan. We hypothesized that there are shared and unique roles of individual CSF-1 isoforms during renal inflammation. To test this, we evaluated transgenic mice only expressing the cell surface or precursors of the secreted CSF-1 isoforms for Mφ accumulation, activation, and Mφ-mediated tubular epithelial cell (TEC) apoptosis during unilateral ureteral obstruction. The only difference between secreted proteoglycan and secreted glycoprotein CSF-1 isoforms is the presence (proteoglycan) or absence (glycoprotein) of an 18-kDa chondroitin sulfate glycosaminoglycan. We report that 1) cell surface CSF-1 isoform is sufficient to restore Mφ accumulation, activation, and TEC apoptosis to wild-type levels and is substantially more effective than the secreted CSF-1 isoforms; 2) the chondroitin sulfate glycosaminoglycan facilitates Mφ accumulation, activation, and TEC apoptosis; 3) increasing the level of secreted proteoglycan CSF-1 in serum amplifies renal inflammation; and 4) cell-cell contact is required for Mφ to up-regulate CSF-1-dependent expression of IFN-γ. Taken together, we have identified central roles for the cell surface CSF-1 and the chondroitin sulfate chain on secreted proteoglycan CSF-1 during renal inflammation.

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Hepatocyte growth factor/scatter factor and its interaction with heparan sulphate and dermatan sulphate

Cited by 33 publications

References 6 publications

A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist

A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist

Heparan sulfate and heparin interactions with proteins

Distinct In Vivo Roles of Colony-Stimulating Factor-1 Isoforms in Renal Inflammation

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