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  • Collectively the results presented here provide

    2019-07-08

    Collectively, the results presented here provide new insights into ligand binding, clustering, spatial distribution, and phosphorylation of DDR1b and DDR2 in response to soluble collagen I. As depicted in the cartoon of Scheme 1, we postulate a model in which the spatial distribution and assembly of DDRs is dependent on the morphological state of collagen and precedes receptor phosphorylation. In this model, we propose that DDR1b cluster formation is promoted by the presence of non-fibrillar collagen present during the early stages of collagen fibrillogenesis. These DDR1b clusters undergo SC75741 to early endosomes, within a few minutes of collagen stimulation, as shown in our earlier studies [16]. At later time points, a fraction of DDR1b receptor clusters may recycle back to the plasma membrane with their cargo. During this process of recycling, a sub-population of DDR1b clusters is enriched with phosphorylated receptor species at Y513. Whether these phosphorylated DDR1b clusters localize in the endosome or the cell-membrane cannot be presently deciphered. Further studies are required to dissect the molecular composition and sub-cellular location of DDR1b clusters, which may be responsible for specific cell-signaling pathways, as has been defined for other members of the receptor tyrosine kinase family [37], [38]. In this regard, it is interesting to note that DDR1 has also been reported to co-internalize with and phosphorylate upon stimulation of insulin-like-growth factor I (IGF-IR) receptor, and the collagen-dependent phosphorylation of DDR1 was impaired in the absence of IGF-IR [39]. Finally, it is important to emphasize the limitations and sensitivity of the techniques and reagents used (e.g., a limited number of anti-phosphotyrosine antibodies) here to follow the spatial–temporal profile of receptor phosphorylation. Another caveat in our studies was that only partial and/or intermittent co-localization of immuno-stained collagen was observed with the clusters and filamentous structures formed by DDRs. We postulate that this could be due to masking of antibody-recognizing epitopes on collagen as a result of DDR binding. Future studies using additional antibodies, fluorescently labeled collagen, submicroscopic high-resolution imaging of molecular complexes, laser capture-microdissection [40] and identification of phosphorylated receptor species by phospho-proteomics approaches at various time points are warranted to elucidate the state of collagen and of these unique collagen receptors upon ligand interactions.
    Acknowledgment This work was supported by NSF CMMI award 1201111 to G.A., AHA predoctoral award 16PRE31160013 to D.Y., and grants from the NIH-NCI (CA1986), Department of Defense (W81XWH-15-1-0226), and the Sky Foundation to R.F. We acknowledge Nabanita Chatterjee at OSU for her assistance with cell-culture experiments.
    Introduction Lymphoma is one of the most malignant cancer which originates from lymphoid tissue. Lymphoma can be basically divided into two types in accordance with the origin of tumor cells, namely B and T-cell lymphoblastic lymphoma (B-LBL and T-LBL). T-LBL is undoubtedly one of the most aggressive and deadliest cancers across the world (You et al., 2015). Despite decades of effort, the outcome of T-LBL remains disappointing. The lack of markers for detecting patients with a high risk of tumor metastasis and recurrence also leads to the disappointing prognosis of T-LBL patients (Al Khabori et al., 2018). Thus, identifying effective and stable therapeutic markers for clinical management of T-LBL is quite imperative. Recent studies documented that epigenetic regulation also participates in tumor initiation and progression (Torre et al., 2015). Non-coding RNAs (ncRNAs), which occupy the majority of human genome, have been shown to act as imperative roles involved in the proliferation, migration and apoptosis of cells (Fang et al., 2018; Zhang et al., 2017; Huang et al., 2014; Qi et al., 2016; Xu et al., 2018a, Xu et al., 2018b). What\'s more, mounting evidence indicate that circular RNAs (circRNAs) expression is dysregulated and contributes to oncogenesis of several carcinomas, including cholangiocarcinoma, breast cancer, and lung cancer, etc. (Xu et al., 2018a, Xu et al., 2018b; Liu et al., 2018; Tian et al., 2019). CircRNAs are often upregulated and downregulated, and may promote/inhibit tumor progression (Pan et al., 2019; Zhu et al., 2019; Wei et al., 2019). However, the role of circRNAs in T-LBL is still not studied and needed to be further explored. In this project, we screened the differentially expressed circRNAs between T-LBL tissues and normal infantile thymus and hsa_circRNA_101303 was identified the highest expressed circRNA in cancer tissues. Hsa_circRNA_101303 is located at chr13: 113963957-113964177 and is a transcript product of LAMP1 gene (circ-LAMP1). This study explored the functions and mechanisms of circ-LAMP1.