Researchers headed by Maria Macias an ICREA researcher at the Institute for Research in Biomedicine (IRB Barcelona) and Joan Massagué, a Howard Hughes Medical Institute investigator at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York, have identified a new molecular mechanism that plays a crucial role in the control of the activation of certain genes associated with cancer.

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Through detailed structural and biochemical studies, the researchers identified a key domain present in a family of proteins called Smads, whose binding determines whether the transcription of genes controlled by the TGF-beta and BMP signaling cascades will be bound by activators or labeled for degradation. These processes are critical to the correct development and maintenance of tissues and organisms.

When looking at inhibitory Smads , the researchers found that the specific domain binds directly and constitutively to their targets. This is in contrast to what happens with receptor-activated Smads, where the proteins must first undergo processing by phosphorylation – a chemical change whereby the proteins are first activated and then labeled for degradation after completing their transcriptional function. The study appears online today (August 23) in the journal Structure.

Smads are key proteins in the signaling pathways of the hormones TGF-beta and BMP, which are known to participate in the control of stem cell pluripotency and differentiation and in the development and maintenance of metazoan organisms. In this study, the researchers looked at the interactions of Smad7 – a protein inhibitor of TGF-beta signaling – with molecules implicated in the cascade, including three ubiquitin ligases and YAP, a transcription coactivator. They identified the domains in the four proteins that interact with the same region of Smad7 and quantified these interactions in terms of affinity values.

The TGF-beta pathway is tightly regulated. Its regulation includes a feedback process whereby the two sets of Smads play complementary roles in the same signaling cascade, as they can either inhibit or trigger gene transcription, depending on cell type and the physiological needs of the tissue or organism. As with most biological processes, achieving a fine balance between the two is key, since uncontrolled gene transcription is a hallmark of serious diseases such as cancer. This latest discovery helps to shed light on how organisms achieve this balance.

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