Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions
Open accessAbstract
Plexin transmembrane receptors and their semaphorin ligands, as well as their co-receptors (Neuropilin, Integrin, VEGFR2, ErbB2, and Met kinase) are emerging as key regulatory proteins in a wide variety of developmental, regenerative, but also pathological processes. The diverse arenas of plexin function are surveyed, including roles in the nervous, cardiovascular, bone and skeletal, and immune systems. Such different settings require considerable specificity among the plexin and semaphorin family members which in turn are accompanied by a variety of cell signaling networks. Underlying the latter are the mechanistic details of the interactions and catalytic events at the molecular level. Very recently, dramatic progress has been made in solving the structures of plexins and of their complexes with associated proteins. This molecular level information is now suggesting detailed mechanisms for the function of both the extracellular as well as the intracellular plexin regions. Specifically, several groups have solved structures for extracellular domains for plexin-A2, -B1, and -C1, many in complex with semaphorin ligands. On the intracellular side, the role of small Rho GTPases has been of particular interest. These directly associate with plexin and stimulate a GTPase activating (GAP) function in the plexin catalytic domain to downregulate Ras GTPases. Structures for the Rho GTPase binding domains have been presented for several plexins, some with Rnd1 bound. The entire intracellular domain structure of plexin-A1, -A3, and -B1 have also been solved alone and in complex with Rac1. However, key aspects of the interplay between GTPases and plexins remain far from clear. The structural information is helping the plexin field to focus on key questions at the protein structural, cellular, as well as organism level that collaboratoria of investigations are likely to answer.
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Plexins and their cognate semaphorin ligands mediate a variety of cell-cell communications in development, adult physiology, and cancer.
“In addition to axon pathfinding during neurodevelopment, plexins and their cognate semaphorin ligands also mediate a variety of cell-cell communications in development, adult physiology, and cancer15–18.”
From Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer’s disease (2024) · cites this paper as [18]
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- Authors
- Hota, P. K., & Buck, M.
- Affiliations
- Case Western Reserve University (US)
- Case Comprehensive Cancer Center (US)
- Corresponding author
- Buck, Matthias
- Venue
- Cellular and Molecular Life Sciences
- Published
- 2012-06-29
- Volume
- 69
- Issue
- 22
- Pages
- 3765-3805
- ISSN
- 1420-682X (ISSN-L)
- 1420-9071
- PMC
- PMC11115013
- OpenAlex
- W2055174533
- Cited by
- 170
- References
- 510
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 10 · 2023: 10 · 2022: 14 · 2021: 19 · 2020: 11 · 2019: 11 · 2018: 9 · 2017: 8 · 2016: 19 · 2015: 14 · 2014: 13 · 2013: 16 · 2012: 2
- FWCI
- 1.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Cellular and Molecular Life Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM073071, R01GM073071)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Axon Guidance and Neuronal Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- plexins, semaphorins, PLXNA2, Plexin-B1, Plexin C1, PLXNA1, Rho GTPases, RhoGAP, Rnd1, Rac1, Ras GTPase, co-receptors, neuropilins, integrins, VEGFR2, ERBB2, MET kinase, protein structure, signal transduction, axon guidance, brain development, cardiovascular development, skeletal development, immune system
- MeSH terms
- Cardiovascular Diseases, Cardiovascular System, Humans, Ligands, Neoplasm Metastasis, Neoplasms, Nerve Tissue Proteins, Nervous System, Nervous System Diseases, Signal Transduction, Cell Adhesion Molecules, Semaphorins
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