A Noncatalytic, Ras-Independent Function of SHP-2 Is Essential in Hematopoietic Progenitors.
Bibliographic record
Abstract
Abstract SHP-2 is a nonreceptor protein tyrosine phosphatase (PTPase) that is essential for embryonic hematopoiesis. SHP-2 acts as a signal relay molecule downstream of diverse growth factor receptors, and potentiates the activity of the Ras/Raf/MAPK pathway. Epistasis studies in model organisms indicate that SHP-2 can act upstream, downstream or parallel to Ras; however, most mammalian systems place SHP-2 upstream of Ras activation. Activating mutations in PTPN11, the gene encoding SHP-2, comprise the most common genetic lesion in juvenile myelomonocytic leukemia (JMML). Other etiologies of JMML include activating mutations in NRAS or KRAS2 and inactivation of the tumor suppressor NF1, which encodes a negative regulator of Ras, supporting a model in which SHP-2 activates Ras in hematopoietic progenitors. We tested the hypothesis that SHP-2 is essential in hematopoiesis because it is required for Ras activation. To do this, we bred mice with conditional hyperactive KrasG12D and inactive Ptpn11flox alleles, in conjunction with the inducible Mx1-Cre transgene. Myeloid progenitors in LSL-KrasG12D; Ptpn11flox/flox; Mx1-Cre mice never deleted both Ptpn11 alleles despite efficient Cre induction and expression of activated K-RasG12D. This indicates selective pressure to retain SHP-2 despite Ras activation and implies that Ptpn11 loss is epistatic to KrasG12D. To test this directly, we acutely disrupted Ptpn11 and expressed KrasG12D in fetal liver cells using Cre-expressing retroviruses, and tested them for myeloid colony-forming activity. This confirmed the need for SHP-2 in myeloid progenitors, and KrasG12D again failed to alleviate this requirement. Surprisingly, expression of either wild type or PTPase-deficient SHP-2 rescued colony growth and restored the aberrant growth of KrasG12D mutant cells. To test whether hematopoiesis in vivo is independent of SHP-2 PTPase function, we created chimeric Mx1-Cre, Ptpn11flox/flox mice in which a small fraction of bone marrow expressed exogenous SHP-2 and GFP. These mice were treated with a short course of pIpC to induce Cre and disrupt Ptpn11, and the contribution of SHP-2 expressing cells in the peripheral blood was monitored by flow cytometry. As expected, exogenous SHP-2 expression in Mx1-Cre, Ptpn11flox/flox bone marrow conferred a strong and durable (>16 wks) competitive advantage after pIpC treatment. Expression of PTPase-deficient SHP-2 also conferred a strong advantage lasting at least several weeks, and these mice are being aged to determine the duration of this response. These data indicate that SHP-2 is required for growth of both normal and neoplastic myeloid progenitors in vivo and in vitro, and suggest that SHP-2 is needed for maintenance of adult hematopoietic stem cells. In contrast to nearly all prior studies in mammalian cells, our data support a model in which SHP-2 has essential hematopoietic functions downstream or parallel to Ras activation. Furthermore, SHP-2 PTPase activity is not required in myeloid progenitors, a finding which also contradicts widely accepted models of SHP-2 function and may indicate that SHP-2 serves an adaptor role. Because PTPase activity is required by leukemogenic but not wild type SHP-2, pharmacologic PTPase inhibition may selectively target neoplastic hematopoietic progenitors.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
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".