RTK

RTK ANTAGONISTS

Enhanced activation of the signaling pathways that mediate the differentiation of mononuclear monocytes into osteoclasts is an underlying cause of several bone diseases and bone metastasis. In particular, dysregulation and overexpression of macrophage colony-stimulating factor (M-CSF) and its c-FMS tyrosine kinase receptor, proteins that are essential for osteoclast differentiation, are known to promote bone metastasis and osteoporosis, making both the ligand and its receptor attractive targets for therapeutic intervention. We develop M-CSF ligand-based, high-affinity antagonists for c-FMS that retain its binding ability but prevent the ligand dimerization that leads to receptor dimerization and activation. These mutants act as functional inhibitors of M-CSF-dependent c-FMS activation and osteoclast differentiation in vitro and in vivo.

Structure of the Tie2–Ang2-BDBC5–αvβ3 complex. The Tie2 structure was aligned into the last frame of the Ang2-BDBC5–integrin αvβ3 MD simulation. Tie2 is shown in cyan, Ang2-BDBC5 in beige, αv in yellow, and β3 in green. Tie2-binding residues of Ang2 are colored magenta, and NTCRGDCLP mutant residues in red. A zoom-in of the binding interface between Ang2-BDBC5 and αvβ3 integrin is also shown. On the right, an all-atom representation of the mutant residues of Ang2-BDBC5 is shown in stick-form.

TIE2

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Engineering a monomeric variant of macrophage colony-stimulating factor (M-CSF) that antagonizes the c-FMS receptor.

Zur Y, Rosenfeld L, Bakhman A, Ilic S, Hayun H, Shahar A, Akabayov B, Kosloff M, Levaot N, Papo N. Biochem J. 2017.

 

Correction: Constitutive Association of Tie1 and Tie2 with Endothelial Integrins is Functionally Modulated by Angiopoietin-1 and Fibronectin.

Dalton AC, Shlamkovitch T, Papo N, Barton WA. PLoS One. 2017.

 

Utilizing combinatorial engineering to develop Tie2 targeting antagonistic angiopoetin-2 ligands as candidates for anti-angiogenesis therapy.

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