WFIKKN1 and WFIKKN2 bind growth factors TGFβ1, BMP2 and BMP4 but do not inhibit their signalling activity.
WFIKKN1 and WFIKKN2 are large extracellular multidomain proteins consisting of a WAP domain, a follistatin domain, an immunoglobulin domain, two Kunitz-type protease inhibitor domains and an NTR domain. Recent experiments have shown that both proteins have high affinity for growth and differentiation factor (GDF)8 and GDF11. Here we study the interaction of WFIKKN proteins with several additional representatives of the transforming growth factor (TGF)β family using SPR measurements. Analyses of SPR sensorgrams suggested that, in addition to GDF8 and GDF11, both WFIKKN proteins bind TGFβ1, bone morphogenetic protein (BMP)2 and BMP4 with relatively high affinity (K(d) ∼ 10(-6) m). To assess the biological significance of these interactions we studied the effect of WFIKKN proteins on the activity of GDF8, GDF11, TGFβ1, BMP2 and BMP4 using reporter assays. These studies revealed that WFIKKN1 and WFIKKN2 inhibited the biological activity of GDF8 and GDF11 in the nanomolar range, whereas they did not inhibit the activities of TGFβ1, BMP2 and BMP4 even in the micromolar range. Our data indicate that WFIKKN proteins are antagonists of GDF8 and GDF11, but in the case of TGFβ1, BMP2 and BMP4 they function as growth factor binding proteins. It is suggested that the physical association of WFIKKN proteins with these growth factors may localize their action and thus help to establish growth factor gradients in the extracellular space.
Institute of Enzymology, Budapest, Hungary.
György
G
Szláma
Katalin
K
Kondás
Mária
M
Trexler
László
L
Patthy
D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction; D020349:Surface Plasmon Resonance; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D053773:Transforming Growth Factor beta1; C424444:WFIKKN2 protein, human