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Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1
M Kretzschmar1, J Doody, J Massagué
1Cell Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Abstract:
The growth factor TGF-beta, bone morphogenetic proteins (BMPs) and related factors regulate cell proliferation, differentiation and apoptosis, controlling the development and maintenance of most tissues. Their signals are transmitted through the phosphorylation of the tumour-suppressor SMAD proteins by receptor protein serine/threonine kinases (RS/TKs), leading to the nuclear accumulation and transcriptional activity of SMAD proteins. Here we report that Smadl, which mediates BMP signals, is also a target of mitogenic growth-factor signalling through epidermal growth factor and hepatocyte growth factor receptor protein tyrosine kinases (RTKs). Phosphorylation occurs at specific serines within the region linking the inhibitory and effector domains of Smad1, and is catalysed by the Erk family of mitogen-activated protein kinases. In contrast to the BMP-stimulated phosphorylation of Smad1, which affects carboxy-terminal serines and induces nuclear accumulation of Smad1, Erk-mediated phosphorylation specifically inhibits the nuclear accumulation of Smad1. Thus, Smadl receives opposing regulatory inputs through RTKs and RS/TKs, and it is this balance that determines the level of Smad1 activity in the nucleus, and so possibly the role of Smad1 in the control of cell fate.
Insights
Bone morphogenetic proteins (BMPs) and growth factors regulate cell fate via SMAD proteins. Erk-mediated phosphorylation of Smad1 inhibits nuclear accumulation, opposing BMP signaling and controlling cell fate.
Area of Science:
- Cell biology
- Molecular signaling
- Developmental biology
Background:
- Growth factors like TGF-beta and BMPs are crucial for tissue development and maintenance.
- SMAD proteins act as key mediators in signaling pathways initiated by these growth factors.
- Receptor serine/threonine kinases (RS/TKs) phosphorylate SMAD proteins, promoting their nuclear accumulation and transcriptional activity.
Purpose of the Study:
- To investigate the regulation of Smad1, a BMP-signaling mediator, by other growth factor pathways.
- To elucidate the opposing regulatory mechanisms controlling Smad1 activity.
- To understand how the balance of these signals influences cell fate decisions.
Main Methods:
- Investigated Smad1 phosphorylation by receptor protein tyrosine kinases (RTKs) activated by epidermal growth factor and hepatocyte growth factor.
- Identified specific phosphorylation sites on Smad1 targeted by Erk mitogen-activated protein kinases.
- Compared the effects of BMP-stimulated phosphorylation versus Erk-mediated phosphorylation on Smad1 nuclear localization.
Main Results:
- Smad1 is a target of mitogenic growth factor signaling via RTKs, mediated by Erk kinases.
- Erk-mediated phosphorylation occurs at specific serines in the inhibitory/effector domain linker region of Smad1.
- Unlike BMP signaling, Erk phosphorylation inhibits Smad1 nuclear accumulation.
Conclusions:
- Smad1 integrates opposing signals from RTKs and RS/TKs.
- The balance between these opposing phosphorylation events dictates Smad1's nuclear levels and its role in cell fate determination.
- This dual regulation provides a critical mechanism for controlling cellular responses to diverse extracellular cues.