Journal of Cell Science was made aware of duplicated α-tubulin control blots in [Fig. 3][1]C and 3G of J. Cell Sci. (2014) 127, [4740-4749][2] ([doi:10.1242/jcs.155721][3]).The journal approached the Weizmann Institute of Science and asked them to review the original data supplied by the

Journal of Cell Science was made aware of duplicated α-tubulin control blots in Fig. 3C and 3G of J. Cell Sci. (2014) 127, 4740-4749 (doi:10.1242/jcs.155721).The journal approached the Weizmann Institute of Science and asked them to review the original data supplied by the authors. The Weizmann Institute formed an inquiry committee, whose report stated:“The committee was able to confirm the authenticity of the findings, based on a large body of data (original experiments, repeats done prior to publication and recently repeated experiments). The intensity ratio between the Nir2 bands in Fig. 3G and the corrected tubulin bands provided by the author is similar to what was published in the error-containing Fig. 3G. This implies that the correction has no impact on the original findings. The committee concluded that indeed this was a simple mistake.”As the inquiry committee decided that the conclusions of the paper were not affected by the error, the appropriate course of action – according to COPE guidelines – is to publish a Correction.The correct figure panel is shown below:The authors apologise for any inconvenience caused.

Epithelial-to-mesenchymal transition (EMT) is a central developmental process implicated in cancer metastasis. Here we show that the tyrosine kinase PYK2 enhances cell migration and invasion and potentiates EMT in human breast carcinoma. EMT inducer, such as EGF, induces rapid phosphorylation of PYK2 and its translocation to early endosomes where it co-localizes with EGFR and sustains its downstream signals. Furthermore, PYK2 enhances EGF-induced STAT3-phosphorylation, while phospho-STAT3 directly binds to PYK2 promoter and regulates PYK2 transcription. STAT3 and PYK2 also enhance c-Met expression, while c-Met augments their phosphorylation, suggesting a positive feedback loop between PYK2-STAT3c- Met. We propose that PYK2 sustains endosomal-derived receptor signalling and participates in a positive feedback that links cell surface receptor(s) to transcription factor(s) activation, thereby prolonging signalling duration and potentiating EMT. Given the role of EMT in breast cancer metastasis, we also found a significant correlation between PYK2 expression, tumour grade and lymph node metastasis, thus, demonstrating the clinicopathological implication of our findings.

Calmodulin lysine methyl transferase (CaM KMT) is ubiquitously expressed and highly conserved from plants to vertebrates. CaM is frequently trimethylated at Lys-115, however, the role of CaM methylation in vertebrates has not been studied. CaM KMT was found to be homozygously deleted in the 2P21 deletion syndrome that includes 4 genes. These patients present with cystinuria, severe intellectual disabilities, hypotonia, mitochondrial disease and facial dysmorphism. Two siblings with deletion of three of the genes included in the 2P21 deletion syndrome presented with cystinuria, hypotonia, a mild/moderate mental retardation and a respiratory chain complex IV deficiency. To be able to attribute the functional significance of the methylation of CaM in the mouse and the contribution of CaM KMT to the clinical presentation of the 2p21deletion patients, we produced a mouse model lacking only CaM KMT with deletion borders as in the human 2p21deletion syndrome. No compensatory activity for CaM methylation was found. Impairment of complexes I and IV, and less significantly III, of the mitochondrial respiratory chain was more pronounced in the brain than in muscle. CaM KMT is essential for normal body growth and somatosensory development, as well as for the proper functioning of the adult mouse brain. Developmental delay was demonstrated for somatosensory function and for complex behavior, which involved both basal motor function and motivation. The mutant mice also had deficits in motor learning, complex coordination and learning of aversive stimuli. The mouse model contributes to the evaluation of the role of methylated CaM. CaM methylation appears to have a role in growth, muscle strength, somatosensory development and brain function. The current study has clinical implications for human patients. Patients presenting slow growth and muscle weakness that could result from a mitochondrial impairment and mental retardation should be considered for sequence analysis of the CaM KMT gene.

The involvement of epithelial-mesenchymal transition (EMT) in breast cancer metastasis has been demonstrated in many studies. However, the intracellular proteins and signaling pathways that regulate EMT have not been fully identified. Here, we show that the lipid-transfer protein Nir2 (also known as PITPNM1) enhances EMT in mammary epithelial and breast cancer cells. Nir2 overexpression decreases the expression of epithelial markers and concomitantly increases the expression of mesenchymal markers, whereas silencing of Nir2 expression by small hairpin RNA (shRNA) has opposite effects. Additionally, Nir2 expression is increased during EMT and affects cell morphology, whereas Nir2 depletion attenuates growth factor-induced cell migration. These effects of Nir2 on EMT-associated processes are mainly mediated through the PI3K/AKT and the ERK1/2 pathways. Nir2 depletion also inhibits cell invasion in vitro and lung metastasis in animal models. Immunohistochemical analysis of breast cancer tissue samples reveals a correlation between high Nir2 expression and tumor grade, and Kaplan-Meier survival curves correlate Nir2 expression with poor disease outcome. These results suggest that Nir2 not only enhances EMT in vitro and breast cancer metastasis in animal models, but also contributes to breast cancer progression in human patients.

Lipid transfer proteins (LTPs) were initially discovered as soluble factors that accelerate the transfer of different lipid species between membranes in vitro. Since then, many LTPs have been isolated, cloned, crystallized and extensively studied for over 30 years. The mechanisms by which LTPs transfer lipids between bilayers in vitro have been established by numerous studies. Yet, their actual functions in intact cells remain largely controversial. Extensive studies on LTPs from plants, yeast and mammals suggest that LTPs regulate multiple cellular processes including vesicular trafficking, signal transduction and lipid metabolism. Our studies on certain LTPs with different lipid‐transfer specificity demonstrated their influence on intracellular lipid distribution; shed light on their mechanisms of action in intact cells, and their coordinated lipid transfer activity. Furthermore, our studies on the Nir2 protein, a large protein consisting of an N‐terminal phsphatidylinositol (PI)‐transfer domain, demonstrate its regulatory role in membrane trafficking events and signal transduction cascades. We will discuss our recent findings and describe our general view on LTPs and their mode of action in intact cells.

Phosphatidic acid (PA) and phosphoinositides are metabolically interconverted lipid second messengers that have central roles in many growth factor (GF)-stimulated signalling pathways. Yet, little is known about the mechanisms that coordinate their production and downstream signalling. Here we show that the phosphatidylinositol (PI)-transfer protein Nir2 translocates from the Golgi complex to the plasma membrane in response to GF stimulation. This translocation is triggered by PA formation and is mediated by its C-terminal region that binds PA in vitro. We further show that depletion of Nir2 substantially reduces the PI(4,5)P2 levels at the plasma membrane and concomitantly GF-stimulated PI(3,4,5)P3 production. Finally, we show that Nir2 positively regulates the MAPK and PI3K/AKT pathways. We propose that Nir2 through its PA-binding capability and PI-transfer activity can couple PA to phosphoinositide signalling, and possibly coordinates their local lipid metabolism and downstream signalling.