A new paradigm in phosphoinositide signaling? (Comment on DOI 10.1002/bies.201100195)
Bibliographic record
Abstract
Membrane associated phosphatidylinositides, notably phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), regulate numerous cellular functions, so their levels must be tightly regulated or diseases such as inflammation, cancer, and diabetes can result 1. In response to extracellular stimuli, phosphoinositide 3-kinase (PI3K) enzymes become activated to produce PtdIns(3,4,5)P3. Phosphoinositol (PI) phosphatases can counter the action of PI3Ks by dephosphorylating PtdIns(3,4,5)P3, but unlike PI3Ks, the enzymatic activity of PI phosphatases were originally thought to be constitutively “on” even in the absence of extracellular signals. Instead of changes in intrinsic enzyme activity, certain PI phosphatases such as SHIP1 or SHIP2 were thought to be primarily regulated by their recruitment to the membrane where they can then access and hydrolyze PtdIns(3,4,5)P3. However, as summarized by Elong Edimo et al., we are now appreciating that mechanisms such as reversible phosphorylations of PI phosphatase on serine and threonine (ser/thr) residues can alter not only their subcellular location, but also their intrinsic enzyme activity 2. SHIP1/2 were both first identified as SH2 domain containing, tyrosine phosphorylated proteins which become recruited to the membrane through SH2 domain interactions with tyrosine phosphorylated receptors or receptor associated signaling complexes. Tyrosine phosphorylation of SHIP1/2 is widely used as a surrogate marker of SHIP1/2 activation, but tyrosine phosphorylation does not alter SHIP1/2 enzyme activity and mainly functions to shunt SHIP1 to proteasome mediated degradation 3. Recently, however, studies have shown that the intrinsic enzyme activity of several PI phosphatases, including SHIP1, were indeed subject to end-product allosteric activation 4. Furthermore, some PI phosphatases can be recruited to the membrane through inherent lipid binding PH-like domains as well as of SH2-phosphotyrosyl interactions 5. Indeed, that is the case with SHIP1. In addition to these mechanisms, a role for ser/thr phosphorylations of PI phosphatases such as SHIP1/2 in regulating their activity and cellular localization is becoming apparent 2. Specifically, phosphorylation of SHIP1 by a cyclic AMP dependent kinase has been shown to increase SHIP1 enzyme activity 6, while SHIP2 also undergoes phosphorylation at several ser/thr residues with phosphorylation of serine 132 required for SHIP2 localization to nuclear speckles 7. Interestingly, SHIP2 has been shown to physically associate with a protein phosphatase PP2A subunit and this interaction may keep its basal phosphorylation low 8. Other PI phosphatases such as SYJ1 and PTEN have also been found to undergo ser/thr phosphorylation and/or associate with PP2A 2. The model that emerges is that PI phosphatases, rather than being basally active, are enzymes whose activity, interaction with cellular signaling complexes and localization are tightly regulated through multiple mechanisms. Many questions remain to be answered. What are the identities of the ser/thr protein kinases and phosphatases which target SHIP1/2 and other PI phosphatases? How does regulation by ser/thr phosphorylation integrate with the allosteric activation of intrinsic enzyme activity? How do ser/thr phosphorylation-mediated changes in localization coordinate with changes mediated by SH2-phosphotyrosyl, or direct PH-like domain interactions with membrane phospholipids? Understanding the role that ser/thr phosphorylation plays in regulating PI phosphatase function will provide insight into human diseases such as inflammation, cancer and diabetes, in which dysregulated PI phosphatase functions have been implicated.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; both teacher heads agree on what is shown here.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".