Alternative titles; symbols
HGNC Approved Gene Symbol: RAPH1
Cytogenetic location: 2q33.2 Genomic coordinates (GRCh38) : 2:203,433,682-203,535,301 (from NCBI)
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned RAPH1, which they designated KIAA1681. The deduced 1,236-amino acid protein shares significant similarity with mouse Grb10 (601523). RT-PCR ELISA detected moderate to high RAPH1 expression in all adult and fetal tissues and specific brain regions examined, except lung. Highest expression was in brain.
By screening databases for proteins containing FPPPP motifs, which bind Enabled (ENA; 609061)/VASP (601703) homology-1 (EVH1) domains, followed by PCR, Krause et al. (2004) cloned full-length RAPH1, which they designated LPD. The deduced 1,250-amino acid protein contains a putative N-terminal coiled-coil motif, a Ras association domain, and a PH domain. The C-terminal half is proline rich, with 8 potential SH3-binding sites, 3 potential profilin (176610)-binding sites, and 4 clusters containing a total of 6 FPPPP motifs. Database analysis indicated there is at least 1 LPD splice variant. Northern blot analysis of mouse tissues detected several transcripts expressed in a tissue-specific manner, with highest expression in brain, heart, ovary, and developing embryo. Western blot analysis determined that Lpd has an apparent molecular mass of about 200 kD.
Krause et al. (2004) confirmed that LPD bound VASP in vitro and in vivo. The 2 proteins colocalized at the tips of lamellipodia and filopodia in several human and rodent cells. LPD was recruited specifically to the interface between enteropathogenic E. coli and their actin pedestals and to the interface between Vaccinia virus and its actin tail. LPD was not recruited to the interface between Listeria or Shigella and their F-actin tails. The PH domain of LPD specifically bound phosphatidylinositol 3,4-bisphosphate, which targeted the PH domain of LPD to ruffles in PDGF (see 190040)-treated rat fibroblasts. LPD overexpression increased lamellipodial protrusion velocity, an effect observed when VASP-related proteins are overexpressed or artificially targeted to the plasma membrane. Conversely, knockdown of mouse Lpd expression impaired lamellipodia formation in mouse melanoma cells, reduced velocity of residual lamellipodial protrusion, and decreased F-actin content. These phenotypes were more severe than the loss of VASP alone, leading Krause et al. (2004) to suggest that LPD regulates other effectors of the actin cytoskeleton in addition to VASP.
By radiation hybrid analysis, Nagase et al. (2000) mapped the RAPH1 gene to chromosome 2.
Krause, M., Leslie, J. D., Stewart, M., Lafuente, E. M., Valderrama, F., Jagannathan, R., Strasser, G. A., Rubinson, D. A., Liu, H., Way, M., Yaffe, M. B., Boussiotis, V. A., Gertler, F. B. Lamellipodin, an Ena/VASP ligand, is implicated in the regulation of lamellipodial dynamics. Dev. Cell 7: 571-583, 2004. [PubMed: 15469845] [Full Text: https://doi.org/10.1016/j.devcel.2004.07.024]
Nagase, T., Kikuno, R., Hattori, A., Kondo, Y., Okumura, K., Ohara, O. Prediction of the coding sequences of unidentified human genes. XIX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 347-355, 2000. [PubMed: 11214970] [Full Text: https://doi.org/10.1093/dnares/7.6.347]