Abstract
The cognate interaction of ROBO1/4 with its ligand SLIT2 is known to be involved in lung cancer progression. However, the precise role of genetic variants, disrupting the molecular interactions is less understood. All cancer-associated missense variants of ROBO1/4 and SLIT2 from COSMIC were screened for their pathogenicity. Homology modelling was done in Modeller 9.17, followed by molecular simulation in GROMACS. Rigid docking was performed for the cognate partners in PatchDock with refinement in HADDOCK server. Post-docking alterations in conformational, stoichiometric, as well as structural parameters, were assessed. The disruptive variants were ranked using a weighted scoring scheme. In silico prioritisation of 825 variants revealed 379 to be potentially pathogenic out of which, about 12% of the variants, i.e. ROBO1 (14), ROBO4 (8), and SLIT2 (23) altered the cognate docking. Six variants of ROBO1 and 5 variants of ROBO4 were identified as "high disruptors" of interactions with SLIT2 wild type. Likewise, 17 and 13 variants of SLIT2 were found to be "high disruptors" of its interaction with ROBO1 and ROBO4, respectively. Our study is the first report on the impact of cancer-associated missense variants on ROBO1/4 and SLIT2 interactions that might be the drivers of lung cancer progression.
Highlights
The cognate interaction of ROBO1/4 with its ligand SLIT2 is known to be involved in lung cancer progression
Myosin 9b (Myo9b) is overexpressed in lung cancer tissue, and it interacts with ROBO1-ICD through its RhoGAP domain, which suppresses the Myo9b RhoGAP activity
The regular interaction of SLIT2 with ROBO1 suppresses Myo9b leading to inhibition of m etastasis[28]
Summary
The cognate interaction of ROBO1/4 with its ligand SLIT2 is known to be involved in lung cancer progression. The SLIT/ROBO signalling pathway has anti-migratory and pro-apoptotic properties in many cancers[15], such as Small Cell Lung Cancer (SCLC). These tumour-suppressive effects could be weakened by mutations[16] within the cognate partners and its mediators. ROBO1 was found to be a specific serum biomarker in S CLC31 It is well-established that the SLIT2-ROBO1 signalling pathway is tumour suppressive in many cancers, including lung c ancer[26,28,29]. The role of the genetic variants on the interaction of SLIT2/ROBO1/4, potentially altering the anti-angiogenic pathway and overall tumour suppressive function, is yet to be elucidated
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