Farp2, the FERM, RhoGEF and pleckstrin domain protein 2, is a Dbl-family guanine nucleotide exchange factor (GEF). It contains a FERM domain, a Dbl-homology (DH) domain and two pleckstrin homology (PH) domains. Farp2 activates Rac1 or Cdc42 in response to upstream signals, regulating processes such as neuronal axon guidance, dendritic morphogenesis, tight junction formation, polarity, osteoclast podosome rearrangements, and potentially HDL cholesterol levels [1,3,4,5]. It is involved in signaling pathways like Sema3A-Nrp1/PlxnA4 signaling and is associated with aPKCι in polarity regulation [1,3].

In the nervous system, using PlxnA4KRK-AAA knock-in mice, the RhoGEF FARP2 was shown to be part of a novel Sema3A-Nrp1/PlxnA4/FARP2/Rac1 signaling pathway that specifically controls dendritic morphogenesis but not axon guidance [1]. In axonal repulsion, Sema3A binding to neuropilin-1 induces dissociation of FARP2 from plexin-A1, activating FARP2's Rac GEF activity for axonal repulsion [2]. In epithelial cells, FARP2, as a partner and substrate of aPKCι, is required for efficient polarisation and junction formation [3]. In osteoclasts, FARP2 deficiency leads to reduced formation of multinucleated osteoclasts and resorption pits, revealing its role in podosome rearrangements [5].

In conclusion, Farp2 is crucial for multiple biological processes, especially in the nervous system development, polarity establishment, and osteoclast function. Mouse models, like the PlxnA4KRK-AAA knock-in mice, have been instrumental in revealing its role in dendritic morphogenesis. These findings contribute to understanding the mechanisms underlying neural development and potentially related diseases [1].

References:

1. Danelon, Victor, Goldner, Ron, Martinez, Edward, Yaron, Avraham, Tran, Tracy S. 2020. Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis. In The Journal of neuroscience : the official journal of the Society for Neuroscience, 40, 5413-5430. doi:10.1523/JNEUROSCI.2730-19.2020. https://pubmed.ncbi.nlm.nih.gov/32499377/

2. Toyofuku, Toshihiko, Yoshida, Junko, Sugimoto, Tamiko, Hori, Masatsugu, Kikutani, Hitoshi. 2005. FARP2 triggers signals for Sema3A-mediated axonal repulsion. In Nature neuroscience, 8, 1712-9. doi:. https://pubmed.ncbi.nlm.nih.gov/16286926/

3. Elbediwy, Ahmed, Zhang, Yixiao, Cobbaut, Mathias, McDonald, Neil Q, Parker, Peter J. 2019. The Rho family GEF FARP2 is activated by aPKCι to control tight junction formation and polarity. In Journal of cell science, 132, . doi:10.1242/jcs.223743. https://pubmed.ncbi.nlm.nih.gov/30872454/

4. He, Xiaojing, Kuo, Yi-Chun, Rosche, Tyler J, Zhang, Xuewu. 2013. Structural basis for autoinhibition of the guanine nucleotide exchange factor FARP2. In Structure (London, England : 1993), 21, 355-64. doi:10.1016/j.str.2013.01.001. https://pubmed.ncbi.nlm.nih.gov/23375260/

5. Takegahara, Noriko, Kang, Sujin, Nojima, Satoshi, Toyofuku, Toshihiko, Kumanogoh, Atsushi. 2010. Integral roles of a guanine nucleotide exchange factor, FARP2, in osteoclast podosome rearrangements. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 24, 4782-92. doi:10.1096/fj.10-158212. https://pubmed.ncbi.nlm.nih.gov/20702777/