Semaphorin 4D signaling requires the recruitment of phospholipase C gamma into the plexin-B1 receptor complex

Molecular and Cellular Biology
Jakub M SwierczStefan Offermanns


The semaphorin 4D (Sema4D) receptor plexin-B1 constitutively interacts with particular Rho guanine nucleotide exchange factors (RhoGEFs) and thereby mediates Sema4D-induced RhoA activation, a process which involves the tyrosine phosphorylation of plexin-B1 by ErbB-2. It is, however, unknown how plexin-B1 phosphorylation regulates RhoGEF activity. We show here that activation of plexin-B1 by Sema4D and its subsequent tyrosine phosphorylation creates docking sites for the SH2 domains of phospholipase Cgamma (PLCgamma). PLCgamma is thereby recruited into the plexin-B1 receptor complex and via its SH3 domain activates the Rho guanine nucleotide exchange factor PDZ-RhoGEF. PLCgamma-dependent RhoGEF activation is independent of its lipase activity. The recruitment of PLCgamma has no effect on the R-Ras GTPase-activating protein activity of plexin-B1 but is required for Sema4D-induced axonal growth cone collapse as well as for the promigratory effects of Sema4D on cancer cells. These data demonstrate a novel nonenzymatic function of PLCgamma as an important mechanism of plexin-mediated signaling which links tyrosine phosphorylation of plexin-B1 to the regulation of a RhoGEF protein and downstream cellular processes.


Jan 25, 2012·Nature Reviews. Cancer·Ermanno GherardiGeorge Vande Woude
Mar 2, 2012·The Journal of Clinical Investigation·Thomas WorzfeldStefan Offermanns
Mar 13, 2012·Molecular Cancer·Chun ZhouMagali Williamson
Jan 21, 2011·Molecular Autism·John P HussmanMargaret A Pericak-Vance
May 21, 2014·The Journal of Cell Biology·Aleksandra TataChenghua Gu
Jan 29, 2014·Proceedings of the National Academy of Sciences of the United States of America·Thomas WorzfeldStefan Offermanns
Mar 8, 2013·The Journal of Biological Chemistry·Constantinos M MikelisJ Silvio Gutkind
Aug 20, 2014·PloS One·Matthias ZielonkaStefan Offermanns
Aug 26, 2010·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Nina PeräläTiina Immonen
Aug 2, 2014·Nature Reviews. Drug Discovery·Thomas Worzfeld, Stefan Offermanns
Jun 19, 2013·The Prostate·Adebiyi DamolaMagali Williamson
Jul 5, 2018·Frontiers in Endocrinology·Konstantinos LontosAttaya Suvannasankha


Mar 12, 1993·Cell·Z SongyangR J Lechleider
Jul 5, 1994·Proceedings of the National Academy of Sciences of the United States of America·M R SmithH F Kung
Dec 1, 1995·Molecular and Cellular Biology·M TanakaB J Mayer
Aug 8, 1998·Trends in Cell Biology·D Cantrell
Oct 16, 1999·Cell·T TakahashiS M Strittmatter
Oct 18, 2000·Proceedings of the National Academy of Sciences of the United States of America·Haris G VikisK L Guan
Oct 19, 2000·Methods in Enzymology·X D Ren, M A Schwartz
Jun 8, 2001·Annual Review of Biochemistry·S G Rhee
Nov 8, 2001·The Journal of Biological Chemistry·Clark D WellsPaul C Sternweis
Apr 9, 2002·Genes & Development·Haris G VikisKun-Liang Guan
Aug 17, 2002·The Journal of Biological Chemistry·Valerie PerrotJ Silvio Gutkind
Aug 28, 2002·Proceedings of the National Academy of Sciences of the United States of America·Jennifer AurandtKun-Liang Guan
Aug 29, 2002·Nature Cell Biology·Silvia GiordanoPaolo Maria Comoglio
Sep 11, 2002·Biochemical and Biophysical Research Communications·Mutsumi HirotaniShinobu Inagaki
Oct 10, 2002·FEBS Letters·Mariette H E DriessensJohn G Collard
Jul 17, 2003·Science's STKE : Signal Transduction Knowledge Environment·Joseph Schlessinger, Mark A Lemmon
Sep 6, 2003·Nature Structural Biology·Christopher A LoveRobert M Esnouf
Feb 3, 2004·Methods in Molecular Biology·Miranda van Triest, Johannes L Bos
Jun 24, 2004·The Journal of Cell Biology·Jakub M SwierczStefan Offermanns
Feb 22, 2005·Neoplasia : an International Journal for Oncology Research·Timo FaltusKlaus Strebhardt
Mar 15, 2005·Proceedings of the National Academy of Sciences of the United States of America·Benoit PoulinSue Goo Rhee
Nov 2, 2005·Trends in Biochemical Sciences·Randen L PattersonSolomon H Snyder
Nov 30, 2005·Nature Reviews. Molecular Cell Biology·Robert P KrugerKun-Liang Guan
Dec 31, 2005·Molecular Neurobiology·Manabu NegishiHironori Katoh
Mar 10, 2006·Molecular Biology of the Cell·Yi WangZhixiang Wang

Related Concepts

SEMA4D gene
Class V Semaphorins
Leukocyte Differentiation Antigens, Human
Axonal Growth Cone
ARHGEF28 gene
Cell Motility
PLXNB1 protein, human
Hormone Receptors, Cell Surface
Phospholipase C gamma D
Protein Phosphorylation

Trending Feeds


Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Sexual Dimorphism in Neurodegeneration

There exist sex differences in neurodevelopmental and neurodegenerative disorders. For instance, multiple sclerosis is more common in women, whereas Parkinson’s disease is more common in men. Here is the latest research on sexual dimorphism in neurodegeneration

HLA Genetic Variation

HLA genetic variation has been found to confer risk for a wide variety of diseases. Identifying these associations and understanding their molecular mechanisms is ongoing and holds promise for the development of therapeutics. Find the latest research on HLA genetic variation here.

Super-resolution Microscopy

Super-resolution microscopy is the term commonly given to fluorescence microscopy techniques with resolutions that are not limited by the diffraction of light. Here are the latest discoveries pertaining to super-resolution microscopy.

Genetic Screens in iPSC-derived Brain Cells

Genetic screening is a critical tool that can be employed to define and understand gene function and interaction. This feed focuses on genetic screens conducted using induced pluripotent stem cell (iPSC)-derived brain cells.

Brain Lower Grade Glioma

Low grade gliomas in the brain form from oligodendrocytes and astrocytes and are the slowest-growing glioma in adults. Discover the latest research on these brain tumors here.

CD4/CD8 Signaling

Cluster of differentiation 4 and 8 (CD8 and CD8) are glycoproteins founds on the surface of immune cells. Here is the latest research on their role in cell signaling pathways.

Alignment-free Sequence Analysis Tools

Alignment-free sequence analyses have been applied to problems ranging from whole-genome phylogeny to the classification of protein families, identification of horizontally transferred genes, and detection of recombined sequences. Here is the latest research.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.