Catalytically inactive human cathepsin D triggers fibroblast invasive growth

The aspartyl-protease cathepsin D (cath-D) is overexpressed and hypersecreted by epithelial breast cancer cells and stimulates their proliferation. As tumor epithelial–fibroblast cell interactions are important events in cancer progression, we investigated whether cath-D overexpression affects also fibroblast behavior. We demonstrate a requirement of cath-D for fibroblast invasive growth using a three-dimensional (3D) coculture assay with cancer cells secreting or not pro-cath-D. Ectopic expression of cath-D in cath-D–deficient fibroblasts stimulates 3D outgrowth that is associated with a significant increase in fibroblast proliferation, survival, motility, and invasive capacity, accompanied by activation of the ras–MAPK pathway. Interestingly, all these stimulatory effects on fibroblasts are independent of cath-D proteolytic activity. Finally, we show that pro-cath-D secreted by cancer cells is captured by fibroblasts and partially mimics effects of transfected cath-D. We conclude that cath-D is crucial for fibroblast invasive outgrowth and could act as a key paracrine communicator between cancer and stromal cells, independently of its catalytic activity

Evolution of the levels of human leukocyte antigen G (HLA-G) in Beninese infant during the first year of life in a malaria endemic area : using latent class analysis

Background: HLA-G, a non-classical HLA class I antigen, is of crucial interest during pregnancy by inhibiting maternal immune response. Its role during infections is discussed, and it has been described that high levels of soluble HLA-G during childhood increase the risk of malaria. To explore more precisely interactions between soluble HLA-G and malaria, latent class analysis was used to test whether distinct sub-populations of children, each with distinctive soluble HLA-G evolutions may suggest the existence of groups presenting variable malaria susceptibility. Method: A study was conducted in Benin from 2010 to 2013 and 165 children were followed from birth to 12 months. Evolution of soluble HLA-G was studied by the latent class method. Results: Three groups of children were identified: one with consistently low levels of soluble HLA-G during follow-up, a second with very high levels and a last intermediate group. In all groups, low birth weight, high number of malaria infections and high exposure to malaria transmission were associated with high level of soluble HLA-G. Placental malaria was not. Presence of soluble HLA-G in cord blood increased the probability of belonging to the highest trajectory. Conclusion: These results, together with previous ones, confirm the important role of HLA-G in the individual susceptibility to malaria. Assaying soluble HLA-G at birth could be a good indicator of newborns more fragile and at risk of infections during childhood

Evolution of the levels of human leukocyte antigen G (HLA-G) in Beninese infant during the first year of life in a malaria endemic area: using latent class analysis

Abstract Background: HLA-G, a non-classical HLA class I antigen, is of crucial interest during pregnancy by inhibiting maternal immune response. Its role during infections is discussed, and it has been described that high levels of soluble HLA-G during childhood increase the risk of malaria. To explore more precisely interactions between soluble HLA-G and malaria, latent class analysis was used to test whether distinct sub-populations of children, each with distinctive soluble HLA-G evolutions may suggest the existence of groups presenting variable malaria susceptibility. Method: A study was conducted in Benin from 2010 to 2013 and 165 children were followed from birth to 12 months. Evolution of soluble HLA-G was studied by the latent class method. Results: Three groups of children were identified: one with consistently low levels of soluble HLA-G during follow-up, a second with very high levels and a last intermediate group. In all groups, low birth weight, high number of malaria infections and high exposure to malaria transmission were associated with high level of soluble HLA-G. Placental malaria was not. Presence of soluble HLA-G in cord blood increased the probability of belonging to the highest trajectory. Conclusion: These results, together with previous ones, confirm the important role of HLA-G in the individual susceptibility to malaria. Assaying soluble HLA-G at birth could be a good indicator of newborns more fragile and at risk of infections during childhood

Oestrogenes, antioestrogenes et cancer du sein. 1) Anticorps monoclonaux et dosage de la pro-cathepsine D. 2) Antioestrogenes et facteurs de croissance

SIGLEINIST T 76405 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

PTPN13/PTPL1: an important regulator of tumor aggressiveness.

International audienceProtein tyrosine phosphorylation plays a major role in many cellular functions implicated in cancer development and progression, but only a few of the known protein tyrosine phosphatases have yet been clearly classified as oncogenes or tumor suppressors. PTPL1 interacts with tumor-associated proteins, suggesting a link between PTPL1, the PTPN13 gene product, and tumorigenesis or cancer progression. However, the impact of PTPL1 on cancer is divided between its capacity to counteract the activity of oncogenic tyrosine kinases and its inhibitory interaction with the death receptor, Fas. In this manuscript, we review the PTPL1-interacting proteins implicated in cancer. In addition, we examine the phenotypic arguments concerning both the PTPL1/Fas interaction and the ability of PTPL1 to inhibit signaling from growth factor receptors or oncogenes with tyrosine kinase activity. Finally, we compare the alterations in expression and the genetic and epigenetic arguments supporting an oncogenic or an anti-oncogenic impact of PTPL1

Protein tyrosine phosphatases and breast cancer

International audienceProtein tyrosine phosphatases (PTPs) consist of a large family of related enzymes, including the group of classical PTPs with its two main subgroups, the transmembrane receptor-type (RPTPs) and the intracellular or non-transmembrane PTPs. Published data on the expression and function of a panel of these enzymes in normal and cancerous breast tissues are discussed in this review. While most studies, albeit on different enzymes, have tended to agree on the evidence for an increased PTP expression in breast cancer, any connection between PTP expression and the enzymes' role in cancer development and progression remains largely open to interpretation. Concomitant increases of protein tyrosine kinase (PTK) and PTP activities in many cancers further indicate that a complex dysregulation in the balance of tyrosine phosphorylation could be responsible for major alterations in various cellular processes controlling tissue homeostasis. In particular, any relationship between the expression of PTPs and their specific diverse roles in the regulation of cell growth and apoptosis in breast cancer needs to be addressed in major fundamental, preclinical and clinical studies

Rôles et mécanismes d'action de la protéine tyrosine phosphatase PTPL1/ptpn13 dans les cancers mammaires et ovariens

Des études cliniques récentes suggèrent un rôle anti-oncogénique de la Protéine Tyrosine Phosphatase (PTP) PTPL1/ptpn13. L'analyse de l'effet inhibiteur du 4-hydroxytamoxifène (OH-Tam) sur l'action des facteurs de croissance a permis, dans un premier temps, d'identifier le rôle clé joué par une nouvelle classe d'enzymes, les PTPs, et par la suite plus spécifiquement de PTPL1 dans le contrôle de la prolifération cellulaire. Mon travail de thèse a permis de démontrer d'une part, que PTPL1 inhibe l'activation de la voie de signalisation Insulin Receptor Substrate-1 (IRS-1)/PI3K/Akt induite par l'Insulin like Growth Factor 1 (IGF1) au travers de la déphosphorylation d'IRS-1, et que cette PTP est suffisante pour inhiber l'effet d'IGF1 sur la survie cellulaire. D'autre part, nous avons élucidé les mécanismes par lesquels l'anti-œstrogène, OH-Tam, inhibe via PTPL1 la croissance des cellules cancéreuses mammaires induite par le Nerve Growth Factor (NGF). PTPL1 est en effet capable de déphosphoryler le récepteur du NGF, p140TrkA, nécessaire à l'activation des MAPK (Mitogen Activated Protein Kinase) et à la régulation de la croissance cellulaire. Finalement, nous avons mis en évidence un rôle clé de PTPL1 dans l'inhibition de l'invasion, de la mobilité et de la prolifération des cellules cancéreuses ovariennes, ce qui est en accord avec les résultats de notre étude rétrospective montrant un intérêt pronostique du dosage de PTPL1 dans ce type de tumeur. L'ensemble de ces résultats confirme le rôle anti-oncogénique de cette PTP. La mise en évidence des cibles moléculaires de PTPL1 et la compréhension des mécanismes de régulation de son expression, de sa localisation, et de son activité, devraient permettre d'envisager de nouvelles approches thérapeutiques visant à réguler l'expression ou l'activité de cet anti-oncogèneRecent clinical studies have suggested an anti-oncogenic role for the Protein Tyrosine Phosphatase (PTP) PTPL1/ptpn13. Analysis of the inhibitory effect of 4-hydroxytamoxifen (OH-Tam) on growth factor action has allowed to identify the key role played by a new class of enzymes, PTPs, and more specially PTPL1 on the control of cell proliferation. The first part of my PhD studies, has demonstrated that PTPL1 inhibits activation of the Insulin Receptor Substrate-1 (IRS-1)/PI3K/Akt pathway induced by Insulin like Growth Factor 1 (IGF1), through the dephosphorylation of IRS-1, and that PTPL1 is sufficient to inhibit the IGF1 effect on cell survival and to induce apoptosis. Moreover, we have clarified the mechanisms by which the anti-estrogen OH-Tam inhibits Nerve Growth Factor (NGF)-induced breast cancer cells growth through PTPL1. PTPL1 is able to induce dephosphorylation of the NGF receptor, p140TrkA, which is necessary for activation of the MAPK (Mitogen Activated Protein Kinase) pathway and regulation of cell growth. Finally, in agreement with our retrospective studies showing the prognostic value of PTPL1 expression in ovarian tumors, we have also showed an inhibitory effect of PTPL1 on invasion, mobility and proliferation of ovarian cancer cells. Altogether, these results are consistent with the anti-oncogenic role played by this PTP. The identification of PTPL1 molecular targets and our understanding of the mechanisms that regulate its expression, its location and its activities, should allow consideration of new therapeutic approaches to regulate the expression or activity of this anti-oncogeneMONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF

Dual Role of the PTPN13 Tyrosine Phosphatase in Cancer

In this review article, we present the current knowledge on PTPN13, a class I non-receptor protein tyrosine phosphatase identified in 1994. We focus particularly on its role in cancer, where PTPN13 acts as an oncogenic protein and also a tumor suppressor. To try to understand these apparent contradictory functions, we discuss PTPN13 implication in the FAS and oncogenic tyrosine kinase signaling pathways and in the associated biological activities, as well as its post-transcriptional and epigenetic regulation. Then, we describe PTPN13 clinical significance as a prognostic marker in different cancer types and its impact on anti-cancer treatment sensitivity. Finally, we present future research axes following recent findings on its role in cell junction regulation that implicate PTPN13 in cell death and cell migration, two major hallmarks of tumor formation and progression

Membrane targeting of protein tyrosine phosphatase PTPL1 through its FERM domain via binding to phosphatidylinositol 4,5-biphosphate.

PTPL1 is the largest known cytoplasmic protein tyrosine phosphatase (PTP) containing a FERM (four point-1, ezrin, radixin and moesin) domain. Enzyme localization and PTP-substrate specificity are thought to play crucial roles in the regulation of PTP activity, which determines their functions. Here we report that PTPL1 is predominantly localized at the apical face of plasma membrane enriched in dorsal microvilli when expressed in HeLa cells. By comparing localization of the full-length enzyme with its FERM domain or FERM-deleted PTPL1 construct, we first concluded that PTPL1-FERM domain is necessary and sufficient to address the wild-type enzyme at the membrane. Two potential phosphatidylinositol 4,5-biphosphate [PtdIns(4,5)P2]-binding motifs were identified within the PTPL1-FERM sequence. We further showed that mutation of both sites altered PTPL1 localization similarly to FERM domain deletion, and impaired its subcellular distribution as confirmed biochemically by cell-fractionation experiments. Using protein-lipid overlays, we demonstrated an interaction of the FERM domain of PTPL1 with PtdIns(4,5)P2, which was lost after mutation of potential PtdIns(4,5)P2-binding motifs. Moreover, neomycin, which masks PtdIns(4,5)P2 polar heads, was shown to decrease by 50% the association of PTPL1 with the cytoskeletal fraction. These results identify the crucial role of the FERM domain in PTPL1 intracellular targeting and demonstrate that localization of PTPL1 is regulated by phosphoinositide metabolism