Calreticulin signaling in health and disease

Wang, Wen-An; Groenendyk, Jody; Michalak, Marek

doi:10.1016/j.biocel.2012.02.009

Cited by 168 publications

(129 citation statements)

References 25 publications

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“…Mechanistically, this likely occurred because CDKN2B-deficient cells express low levels of CALR, which is a well-described ligand for the LRP1 receptor (43,44). As a consequence, we observed that these otherwise healthy macrophages displayed a blunted increase in Abca1 expression and were more likely to differentiate into foam cells -a maladaptive and proatherosclerotic process (45).…”

Section: Figurementioning

confidence: 78%

Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis

Kojima¹,

Downing²,

Kundu³

et al. 2014

J. Clin. Invest.

136

134

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Genetic variation at the chromosome 9p21 risk locus promotes cardiovascular disease; however, it is unclear how or which proteins encoded at this locus contribute to disease. We have previously demonstrated that loss of one candidate gene at this locus, cyclin-dependent kinase inhibitor 2B (Cdkn2b), in mice promotes vascular SMC apoptosis and aneurysm progression. Here, we investigated the role of Cdnk2b in atherogenesis and found that in a mouse model of atherosclerosis, deletion of Cdnk2b promoted advanced development of atherosclerotic plaques composed of large necrotic cores. Furthermore, human carriers of the 9p21 risk allele had reduced expression of CDKN2B in atherosclerotic plaques, which was associated with impaired expression of calreticulin, a ligand required for activation of engulfment receptors on phagocytic cells. As a result of decreased calreticulin, CDKN2B-deficient apoptotic bodies were resistant to efferocytosis and not efficiently cleared by neighboring macrophages. These uncleared SMCs elicited a series of proatherogenic juxtacrine responses associated with increased foam cell formation and inflammatory cytokine elaboration. The addition of exogenous calreticulin reversed defects associated with loss of Cdkn2b and normalized engulfment of Cdkn2b-deficient cells. Together, these data suggest that loss of CDKN2B promotes atherosclerosis by increasing the size and complexity of the lipid-laden necrotic core through impaired efferocytosis.

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Section: Figurementioning

confidence: 78%

Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis

Kojima¹,

Downing²,

Kundu³

et al. 2014

J. Clin. Invest.

136

134

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“…36 The protein resides in the lumen of the endoplasmic reticulum, and its C-terminal domain is responsible for calcium buffering activity, which controls calcium homeostasis. The mechanism by which a mutant calreticulin, characterized by lower calcium-binding activity and devoid of the endoplasmic reticulum retention motif KDEL, determines abnormal proliferation of megakaryocytes and overproduction of PLTs is largely unclear at present.…”

Section: Discussionmentioning

confidence: 99%

JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes

Rumi

Pietra²,

Ferretti³

et al. 2014

Blood

525

497

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“…15,16 Whereas wild-type (WT) CALR is essentially involved in the quality control of proteins and in calcium storage in the ER, 17 the CALR mutants are able to activate the JAK2/STAT pathway via an unknown mechanism like the other MPN driver mutations. 15 The same signaling mutations are found in ETs and PMFs, underscoring they have a close pathogenesis requiring megakaryocyte hyperplasia although they are clinically different diseases.…”

Section: Introductionmentioning

confidence: 99%

Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients

Cabagnols

Favale

Pasquier

et al. 2016

Blood

161

136

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Key Points• Enrichment of atypical MPL mutations in essential thrombocythemia.• MPLS204P and MPLY591N mutants are weak gain-offunction mutants.Mutations in signaling molecules of the cytokine receptor axis play a central role in myeloproliferative neoplasm (MPN) pathogenesis. Polycythemia vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in essential thrombocythemia (ET) with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes. Here, we studied the mutational profile of 17 ET patients negative for JAK2V617F, MPLW515K/L, and CALR mutations, using whole-exome sequencing and next-generation sequencing (NGS) targeted on JAK2 and MPL. We found several signaling mutations including JAK2V617F at very low allele frequency, 1 homozygous SH2B3 mutation, 1 MPLS505N, 1 MPLW515R, and 2 MPLS204P mutations. In the remaining patients, 4 presented a clonal and 7 a polyclonal hematopoiesis, suggesting that certain triple-negative ETs are not MPNs. NGS on 26 additional triple-negative ETs detected only 1 MPLY591N mutation. Functional studies on MPLS204P and MPLY591N revealed that they are weak gain-of-function mutants increasing MPL signaling and conferring either TPO hypersensitivity or independence to expressing cells, but with a low efficiency. Further studies should be performed to precisely determine the frequency of MPLS204 and MPLY591 mutants in a bigger cohort of MPN. (Blood. 2016;127(3):333-342)

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Calreticulin signaling in health and disease

Cited by 168 publications

References 25 publications

Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis

Cyclin-dependent kinase inhibitor 2B regulates efferocytosis and atherosclerosis

JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes

Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients

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