Neurodevelopmental disorders, immunity, and cancer are connected

Nussinov, Ruth; Tsai, Chung‐Jung; Jang, Hyunbum

doi:10.1016/j.isci.2022.104492

Cited by 19 publications

(21 citation statements)

References 252 publications

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“…In this work, we focus on wild-type kinases, which may help in countering aberrant proliferation from overexpression in cancer and other diseases, including neurodevelopmental disorders. , Kinases are however frequently mutated . Kinase domains can harbor single, or frequently double, or multiple mutations. , Mutations occur in multiple kinases in cancer cells, in the same or different pathways. , Since same-protein mutations perturb the conformations, they may considerably alter the binary networks and the corresponding comparison profiles.…”

Section: Discussionmentioning

confidence: 99%

Strategy toward Kinase-Selective Drug Discovery

Zhang

Liu

Jang

et al. 2023

J. Chem. Theory Comput.

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Kinase drug selectivity is the ground challenge in cancer research. Due to the structurally similar kinase drug pockets, off-target inhibitor toxicity has been a major cause for clinical trial failures. The pockets are similar but not identical. Here, we describe a transformation invariant protocol to identify distinct geometric features in the drug pocket that can distinguish one kinase from all others. We integrate available experimental structures with the artificial intelligence-based structural kinome, performing a kinomewide structural bioinformatic analysis to establish the structural principles of kinase drug selectivity. We generate the structural landscape from the experimental kinase−ligand complexes and propose a binary network that encapsulates the information. The results show that all kinases contain binary units that are shared by less than seven other kinases in the kinome. 331 kinases contain unique binary units that may distinguish them from all others. The structural features encoded by these binary units in the network represent the inhibitor-accessible geometric space that may capture the kinome-wide selectivity. Our proposed binary network with the unsupervised clustering can serve as a general structural bioinformatic protocol for extracting the distinguishing structural features for any protein from their families. We apply the binary network to epidermal growth factor receptor tyrosine kinase inhibitor selectivity by targeting the gate area and the AKT1 serine/ threonine kinase selectivity by binding to the αC-helix region and the allosteric pocket. Finally, we develop the cross-platform software, KDS (Kinase Drug Selectivity), for customized visualization and analysis of the binary networks in the human kinome (https://github.com/CBIIT/KDS).

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Section: Discussionmentioning

confidence: 99%

Strategy toward Kinase-Selective Drug Discovery

Zhang

Liu

Jang

et al. 2023

J. Chem. Theory Comput.

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“…Then, we compared the expression scores of the pathways in the shared subnetwork by using gene expression profiles. Our premise is that NDD mutations offer modest but prolonged signaling, whereas cancer mutations are associated with high signaling levels (Nussinov et al, 2022a(Nussinov et al, , 2022b(Nussinov et al, , 2022c(Nussinov et al, , 2022d. Driver mutations are frequent, which is why they are often identified as drivers unless there is experimental data for potent rare mutations (Nussinov et al, 2019b;Nussinov and Tsai, 2015).…”

Section: Conceptualization Construction and Comparisons Of The Networ...mentioning

confidence: 99%

“…Hundreds of genes are implicated in NDDs; however, they are involved in few conserved pathways regulating transcription, including chromatin accessibility, and synaptic signaling (Nussinov et al, 2022d;Parenti et al, 2020;Sahin and Sur, 2015). PI3K/mTOR and Ras/MAPK are frequently linked with synaptic dysregulation (Longo and Klann, 2021;Nussinov et al, 2022aNussinov et al, , 2022dSahin and Sur, 2015).…”

Section: Moderate and Strong Escalation In Signaling Levels Reflect T...mentioning

confidence: 99%

“…They may originate from dysregulation of neuron differentiation, during synapse formation and maturation, or other complex processes in the course of brain evolution, such as emergence from progenitor cells, neuron phenotypic specification, migration, and specific synaptic contacts. Flaws can result in faulty wired neuronal circuits (Nussinov et al, 2023(Nussinov et al, , 2022a. Despite differing from processes associated with the emergence of cancer, data indicate that NDDs and cancer are related, with immunity likely the common factor.…”

Section: Introductionmentioning

confidence: 99%

“…Despite differing from processes associated with the emergence of cancer, data indicate that NDDs and cancer are related, with immunity likely the common factor. The immune and nervous systems coevolve as the embryo develops (Nussinov et al, 2022a). The outcomes, cancer or NDDs, reflect the different cell cycle consequences, proliferation in cancer and differentiation in NDDs.…”

Section: Introductionmentioning

confidence: 99%

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Neurodevelopmental disorders and cancer networks share pathways; but differ in mechanisms, signaling strength, and outcome

Yavuz

Arici

Demirel

et al. 2023

Preprint

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Neurodevelopmental disorders (NDDs) and cancer are connected, with immunity as their common factor. Their clinical presentations differ; however, individuals with NDDs are more likely to acquire cancer. Schizophrenia patients have ~50% increased risk; autistic individuals also face an increased cancer likelihood. NDDs are associated with specific brain cell types at specific locations, emerging at certain developmental time windows during brain evolution. Their related mutations are germline; cancer mutations are sporadic, emerging during life. At the same time, NDDs and cancer share proteins, pathways, and mutations. Here we ask exactly which features they share, and how despite their commonality, they differ in outcomes. Our pioneering bioinformatics exploration of the mutations, reconstructed disease-specific networks, pathways, and transcriptome profiles of autism spectrum disorder (ASD) and cancers, points to elevated signal strength in pathways related to proliferation in cancer, and differentiation in ASD. Signaling strength, not the activating mutation, is the key factor in deciding cancer versus NDDs.

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