Good news! Cancer is history (soon)!
"... Scientists have now figured out how one of the main drivers of prostate cancer, the enzyme Protein Serine Kinase H1 (PSKH1), can be switched on, and off. ...
“When a signalling molecule, such as PSKH1, interacts with certain proteins on a cell surface, this binding triggers a chain of events that can amplify the cell activity and lead to the formation of tumours.” ...
PSKH1 overactivity is associated with tumour progression and metastasis (spread) in prostate cancer. It is also linked to lung and kidney cancers. ...
found that PSKH1 becomes active when it binds to a protein called Calmodulin, which triggers the cascade of signals that promote tumour formation.
But when PSKH1 binds to a protein called Reticulocalbin, this activity is switched off. ..."
"At a glance
- Protein Serine Kinase H1 (PSKH1) is found in cancers of the prostate, lung and kidney.
- Researchers ... have discovered how PSKH1 can have its activity switched on and off depending on which proteins it interacts with in cells.
- The findings open the door to the development of improved cancer therapies.
..."
From the significance and abstract:
"Significance
The approximately one-third of human kinases that are considered understudied or “dark” kinases offer a treasure trove of possibility for uncovering new mechanisms of kinase regulation.
Here, we describe how protein interactors can activate or suppress catalysis by the dark kinase, Protein Serine Kinase H1 (PSKH1).
By direct binding to the kinase domain, the Ca2+ sensor protein, Calmodulin, elevates PSKH1 activity, while members of the Golgi-resident CREC family inhibit activity. An unrelated interactor, UNC119B, best characterized as an acyl chain binder, was also identified to act as an allosteric activator of the PSKH1 kinase domain. These studies expand the repertoire of mechanisms employed in kinase regulation and rationalize how extremes in Ca2+ flux can be decoded to tune kinase activities.
Abstract
Protein Serine Kinase H1 (PSKH1) was recently identified as a crucial factor in kidney development and is overexpressed in prostate, lung, and kidney cancers. However, little is known about PSKH1 regulatory mechanisms, leading to its classification as a “dark” kinase.
Here, we used biochemistry and mass spectrometry to define PSKH1’s consensus substrate motif, protein interactors, and how interactors, including Ca2+ sensor proteins, promote or suppress activity.
Intriguingly, despite the absence of a canonical Calmodulin binding motif, Ca2+-Calmodulin activated PSKH1 while, in contrast, the ER-resident Ca2+ sensor of the Cab45, Reticulocalbin, Erc55, Calumenin (CREC) family, Reticulocalbin-3, suppressed PSKH1 catalytic activity. In addition to antagonistic regulation of the PSKH1 kinase domain by Ca2+ sensing proteins, we identified UNC119B as a protein interactor that activates PSKH1 via direct engagement of the kinase domain.
Our findings identify complementary allosteric mechanisms by which regulatory proteins tune PSKH1’s catalytic activity and raise the possibility that different Ca2+ sensors may act more broadly to tune kinase activities by detecting and decoding extremes of intracellular Ca2+ concentrations."
Scientists discover how to “switch off” a known driver of prostate and other cancers (original news release)
PSKH1 kinase activity is differentially modulated via allosteric binding of Ca2+ sensor proteins (open access)
Fig. 5 Allosteric binders converge on common sites on PSKH1.
Calmodulin binds to PSKH1 (in grey) to ‘switch on’ its activity. Reticulocalbin binds to PSKH1 to ‘switch off’ its activity.
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