Cluster Buster

Science's STKE  22 Jul 2003:
Vol. 2003, Issue 192, pp. tw285-TW285
DOI: 10.1126/stke.2003.192.tw285

Bone morphogenic proteins (BMPs) are part of a large family of transforming growth factor-β (TGF-β) morphogens. Despite the large number of ligands (19 BMPs in mammals), there are only three BMP type I receptors (BRIs) and three BMP type II receptors (BRIIs)--all receptors are serine-threonine kinases and BRII receptors are constitutively active. Oligomerization and preformed receptor clustering contribute to signaling specificity, such that a single BMP can stimulate smad-dependent and -independent pathways. Nohe et al. used image-correlation spectroscopy (IMS) to analyze how expression of these receptors influenced overall density of receptor clusters ("cluster density"), which, in cells with similar numbers of receptors, inversely correlates with the number of receptors per cluster (at high cluster density, the clusters are smaller with fewer receptors; at low cluster density there are many receptors per cluster). In transfected cos7 cells, BRIa receptors had a low cluster density, and expression of catalytically active forms of BRII, but not catalytically inactive forms, led to an increase in cluster density, interpreted to reflect dispersal of preformed BRIa receptor clusters. Constitutively active mutants of BRIa (BRI-ca) also dispersed upon BRII expression, which suggests that BRII was not simply stimulating BRI catalytic activity to cause the redistribution. The addition of BMP-2 to the transfected cells decreased cluster density in cells coexpressing the BRIa (or BRI-ca) and BRII, which suggests that the ligand stimulates cluster formation. Similar rearrangements were observed in A341 cells, which constitutively express BRI1a and increase BRII expression in response to serum deprivation. Thus, clusters of BRIa were dispersed upon serum starvation and reformed upon treatment of the serum-starved cells with BMP-2. Finally, experiments with reporter genes in transfected primary limb mesenchymal cells or A431 cells suggested that smad signaling required expression of BRII and BRI1a and that BRIa-ca could not independently activate smad signaling in the absence of BRII. Together, these results suggest that receptor reorganization contributes to the downstream signaling output of BMP stimulation.

A. Nohe, E. Keating, T. M. Underhill, P. Knaus, N. O. Petersen, Effect of the distribution and clustering of the type I A BMP receptor (ALK3) with the type II BMP receptor on the activation of signalling pathways. J. Cell Sci. 116, 3277-3284 (2003). [Abstract] [Full Text]