The non-canonical WNT/planar cell polarity (WNT/PCP) pathway plays important roles in morphogenetic processes in vertebrates. Among WNT/PCP components, protein tyrosine kinase 7 (PTK7) is a tyrosine ...kinase receptor with poorly defined functions lacking catalytic activity. Here we show that PTK7 associates with receptor tyrosine kinase-like orphan receptor 2 (ROR2) to form a heterodimeric complex in mammalian cells. We demonstrate that PTK7 and ROR2 physically and functionally interact with the non-canonical WNT5A ligand, leading to JNK activation and cell movements. In the Xenopus embryo, Ptk7 functionally interacts with Ror2 to regulate protocadherin papc expression and morphogenesis. Furthermore, we show that Ptk7 is required for papc activation induced by Wnt5a. Interestingly, we find that Wnt5a stimulates the release of the tagged Ptk7 intracellular domain, which can translocate into the nucleus and activate papc expression. This study reveals novel molecular mechanisms of action of PTK7 in non-canonical WNT/PCP signaling that may promote cell and tissue movements.
Background: The planar cell polarity pathway plays important roles in morphogenetic processes.
Results: PTK7 and ROR2 form a heterodimeric complex and bind to WNT5A, promoting JNK phosphorylation and regulating expression of paraxial protocadherin.
Conclusion: PTK7 and ROR2 promote cell movement in mammalian cells and coordinate cell polarity during morphogenetic movements.
Significance: We reveal new mechanisms of action of PTK7 in WNT/PCP signaling.
Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in ...various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.
The receptor protein tyrosine kinase 7 (PTK7) was recently shown to participate in noncanonical Wnt/planar cell polarity signalling during mouse and frog embryonic development. In this study, we ...report that PTK7 interacts with β‐catenin in a yeast two‐hybrid assay and mammalian cells. PTK7‐deficient cells exhibit weakened β‐catenin/T‐cell factor transcriptional activity on Wnt3a stimulation. Furthermore, Xenopus PTK7 is required for the formation of Spemann's organizer and for Siamois promoter activation, events that require β‐catenin transcriptional activity. Using epistatic assays, we demonstrate that PTK7 functions upstream from glycogen synthase kinase 3. Taken together, our data reveal a new and conserved role for PTK7 in the Wnt canonical signalling pathway.
The tyrosine kinase receptor PTK7 implicated in planar cell polarity is shown here to play a role also in the Wnt canonical signaling pathway both during Xenopus embryo development and in mammalian cells.
In ciliated mammalian cells, the precise migration of the primary cilium at the apical surface of the cells, also referred to as translational polarity, defines planar cell polarity (PCP) in very ...early stages. Recent research has revealed a co-dependence between planar polarization of some cell types and cilium positioning at the surface of cells. This important role of the primary cilium in mammalian cells is in contrast with its absence from Drosophila melanogaster PCP establishment. Here, we show that deletion of GTP-binding protein alpha-i subunit 3 (Gαi3) and mammalian Partner of inscuteable (mPins) disrupts the migration of the kinocilium at the surface of cochlear hair cells and affects hair bundle orientation and shape. Inhibition of G-protein function in vitro leads to kinocilium migration defects, PCP phenotype and abnormal hair bundle morphology. We show that Gαi3/mPins are expressed in an apical and distal asymmetrical domain, which is opposite and complementary to an aPKC/Par-3/Par-6b expression domain, and non-overlapping with the core PCP protein Vangl2. Thus G-protein-dependent signalling controls the migration of the cilium cell autonomously, whereas core PCP signalling controls long-range tissue PCP.
Abstract Introduction Elderly acute myeloid leukemia (AML) patients with poor‐risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes ...of elderly unfit patients treatment, it is unknown whether it could be effective in poor‐risk cytogenetics 60–75 years old patients. Materials and Methods We included 60–75‐year‐old AML patients eligible to allogenic stem cell transplantation (allo‐SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. Results Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0–103) and 26 days (range, 0–63). The median duration of the first hospitalization was 32 days (ranges, 7–79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo‐SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo‐SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro‐intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06). Conclusion VEN‐based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60–75 with adverse cytogenetics.
Abstract Venetoclax‐azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE‐A study, treatment was given until progression but there are no data on its ...optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax‐azacitidine due to poor tolerance. Sixty‐two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort ( n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow‐up of 23 months (IQR, 20–32), median overall survival and treatment‐free survival were 44 (IQR, 16‐NR) and 16 (IQR, 8–27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2‐year treatment‐free survival of 80%. In the RR cohort ( n = 22), median overall survival and treatment‐free survival were 19 (IQR, 17–31) and 10 (IQR, 5‐NR) months, respectively. Prior number of venetoclax‐azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment‐free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials.
PTK7 is a tyrosine kinase receptor implicated in planar cell polarity, a process with multiple implications at the cellular and organism levels. Loss of function of PTK7 leads to profound ...morphogenetic defects in the mouse, such as neural tube defects, misorientation of stereocilia in the inner ear, and impaired polarized cell movements. The planar cell polarity pathway is classically assigned to a non-canonical Wnt pathway, which does not rely on b-catenin transcriptional activity. We recently revealed that PTK7 is implicated in b-catenin-dependent developmental processes in mammalian and Xenopus systems. Based on data recently obtained by our group as well as others, we discuss how PTK7 could be involved in canonical and non-canonical Wnt pathways, and which implications are expected from these data in physiology and physiopathology.
Hematopoietic stem cells (HSCs) located in adult bone marrow or fetal liver in mammals produce all cells from the blood system. At the top of the hierarchy are long-term HSCs endowed with lifelong ...self-renewal and differentiation properties. These features are controlled through key microenvironmental cues and regulatory pathways, such as Wnt signaling. We showed previously that PTK7, a tyrosine kinase receptor involved in planar cell polarity, plays a role in epithelial Wnt signaling; however, its function in hematopoiesis has remained unexplored. In this article, we show that PTK7 is expressed by hematopoietic stem and progenitor cells, with the highest level of protein expression found on HSCs. Taking advantage of a Ptk7-deficient mouse strain, we demonstrate that loss of Ptk7 leads to a diminished pool of HSCs but does not affect in vitro or in vivo hematopoietic cell differentiation. This is correlated with increased quiescence and reduced homing abilities of Ptk7-deficient hematopoietic stem and progenitor cells, unraveling novel and unexpected functions for planar cell polarity pathways in HSC fate.
Hematopoiesis takes place in the bone marrow of adult mammals and is the process by which blood cells are replenished every day throughout life. Differentiation of hematopoietic cells occurs in a ...stepwise manner through intermediates of differentiation that could be phenotypically identified. This has allowed establishing hematopoietic cell classification with hematopoietic stem cells (HSCs) at the top of the hierarchy. HSCs are mostly quiescent and serve as a reservoir for maintenance of lifelong hematopoiesis. Over recent years, it has become increasingly clear that HSC quiescence is not only due to intrinsic properties, but is also mediated by cognate interactions between HSCs and surrounding cells within micro-anatomical sites called “niches”. This hematopoietic/stromal crosstalk model also applies to more mature progenitors such as B cell progenitors, which are thought to reside in distinct “niches”. This prompted many research teams to search for specific molecular mechanisms supporting leuko-stromal crosstalk in the bone marrow and acting at specific stage of differentiation to regulate hematopoietic homeostasis. Here, we review recent data on adhesion mechanisms involved in HSCs and B cell progenitors interactions with surrounding bone marrow stromal cells.
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