Hedgehog signaling in development and cancer.

The retinoblastoma (RB) tumour suppressor gene is functionally inactivated in a broad range of paediatric and adult cancers, and a plethora of cellular functions and partners have been identified for the RB protein. Data from human tumours and studies from mouse models indicate that loss of RB function contributes to both cancer initiation and progression. However, we still do not know the identity of the cell types in which RB normally prevents cancer initiation in vivo, and the specific functions of RB that suppress distinct aspects of the tumorigenic process are poorly understood.

Cellular mechanisms of tumour suppression by the retinoblastoma gene

https://www.cell.com/trends/pharmacological-sciences/pdf/S0165-6147(11)00080-0.pdf

β-arrestin-mediated receptor trafficking and signal transduction

Expression of engrailed proteins in arthropods, annelids and chordates

Hedgehog proteins constitute one of a small number of families of secreted signals that have a central role in the development of metazoans. Genetic analyses in flies, fish and mice have uncovered the major components of the pathway that transduces Hedgehog signals, and recent genome sequence projects have provided clues about its evolutionary origins. In this Review we provide an updated overview of the mechanisms and functions of this signalling pathway, highlighting the conserved and divergent features of the pathway, as well as some of the common themes in its deployment that have emerged from recent studies.

Mechanisms and functions of Hedgehog signalling across the metazoa

Deregulation of the Sonic hedgehog pathway has been implicated in an increasing number of human cancers. In this pathway, the seven-transmembrane (7TM) signaling protein Smoothened regulates cellular proliferation and differentiation through activation of the transcription factor Gli. The activity of mammalian Smoothened is controlled by three different hedgehog proteins, Indian, Desert, and Sonic hedgehog, through their interaction with the Smoothened inhibitor Patched. However, the mechanisms of signal transduction from Smoothened are poorly understood. We show that a kinase which regulates signaling by many “conventional” 7TM G-protein-coupled receptors, G protein-coupled receptor kinase 2 (GRK2), participates in Smoothened signaling. Expression of GRK2, but not catalytically inactive GRK2, synergizes with active Smoothened to mediate Gli-dependent transcription. Moreover, knockdown of endogenous GRK2 by short hairpin RNA (shRNA) significantly reduces signaling in response to the Smoothened agonist SAG and also inhibits signaling induced by an oncogenic Smoothened mutant, Smo M2. We find that GRK2 promotes the association between active Smoothened and β-arrestin 2. Indeed, Gli-dependent signaling, mediated by coexpression of Smoothened and GRK2, is diminished by β-arrestin 2 knockdown with shRNA. Together, these data suggest that GRK2 plays a positive role in Smoothened signaling, at least in part, through the promotion of an association between β-arrestin 2 and Smoothened.

Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.

Smoothened, a heptahelical membrane protein, functions as the transducer of Hedgehog signaling. The kinases that modulate Smoothened have been thoroughly analyzed in flies. However, little is known...

/pdf/smoothened-signaling-in-vertebrates-is-facilitated-by-a-g-1mt833atyc.pdf

Smoothened Signaling in Vertebrates Is Facilitated by a G Protein-coupled Receptor Kinase

The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1.

Growth Arrest Specific 8 (Gas8) and G protein-coupled receptor kinase 2 (GRK2) cooperate in the control of Smoothened signaling.

The E2F4 and E2F5 proteins specifically associate with the Rb-related p130 protein in quiescent cells to repress transcription of various genes encoding proteins important for cell growth. A series of reports has provided evidence that Rb-mediated repression involves both histone deacetylase (HDAC)–dependent and HDAC-independent events. Our previous results suggest that one such mechanism for Rb-mediated repression, independent of recruitment of HDAC, involves the recruitment of the COOH-terminal binding protein (CtBP) corepressor, a protein now recognized to play a widespread role in transcriptional repression. We now find that CtBP can interact with the histone acetyltransferase, cyclic AMP–responsive element–binding protein (CREB) binding protein, and inhibit its ability to acetylate histone. This inhibition is dependent on a NH2-terminal region of CtBP that is also required for transcription repression. These results thus suggest two complementary mechanisms for E2F/p130-mediated repression that have in common the control of histone acetylation at target promoters.

https://mcr.aacrjournals.org/content/molcanres/3/10/575.full.pdf

Alison R. Meloni

Papers

Smoothened signal transduction is promoted by G protein-coupled receptor kinase 2.

Smoothened Signaling in Vertebrates Is Facilitated by a G Protein-coupled Receptor Kinase

The Rb-related p130 protein controls telomere lengthening through an interaction with a Rad50-interacting protein, RINT-1.

Growth Arrest Specific 8 (Gas8) and G protein-coupled receptor kinase 2 (GRK2) cooperate in the control of Smoothened signaling.

A mechanism of COOH-terminal binding protein-mediated repression.