Alternative titles; symbols
HGNC Approved Gene Symbol: PPFIA1
Cytogenetic location: 11q13.3 Genomic coordinates (GRCh38) : 11:70,270,690-70,384,396 (from NCBI)
Liprins are multivalent proteins with the potential to form complex structures. They are subdivided into alpha-liprins, like PPFIA1, and beta-liprins, like PPFIBP1 (603141). The C-terminal non-coiled-coil regions of alpha-liprins bind to the membrane-distal phosphatase domains of LAR family members (see LAR, or PTPRF; 179590), as well as to the C-terminal non-coiled-coil regions of beta-liprins. In addition, both alpha- and beta-liprins homodimerize via their N-terminal coiled-coil regions (Serra-Pages et al., 1998).
Using the cytoplasmic region of LAR to screen a HeLa cell cDNA library, Serra-Pages et al. (1995) cloned 2 splice variants of PPFIA1, which they called LIP1A and LIP1B. The deduced proteins contain 1,185 and 1,202 amino acids, respectively. LIP1B lacks the C-terminal methionine found in LIP1A, but it has 18 additional C-terminal amino acids. Both proteins contain a series of N-terminal coiled-coil structures. Northern blot analysis detected ubiquitous expression of a 5.3-kb LIP1B transcript. A minor transcript of 4.0 kb was detected in several tissues, most notably skeletal muscle, and a minor transcript of 6.8 kb was detected in pancreas and kidney. Immunoprecipitation analysis and SDS-PAGE of breast carcinoma cells and transfected COS-7 cells detected radiolabeled LIP1 proteins of 160 and 175 kD. Both proteins were phosphorylated on serines.
Serra-Pages et al. (2005) stated that liprin-alpha-1 has 3 tandem sterile alpha motif (SAM) domains following the N-terminal coiled-coil segment. They called the region containing the SAM domains the liprin homology (LH) region due to its conservation in all liprin family members.
Using immunoprecipitation analysis of cotransfected COS cells, Serra-Pages et al. (1995) showed that LIP1B interacted with the membrane-distal D2 protein tyrosine phosphatase (PTPase) domain of LAR. LIP1B also associated with itself. LIP1B did not significantly affect the PTPase activity of full-length LAR, but it appeared to localize LAR to focal adhesions. In human cells, endogenous LAR and LIP1 localized to the proximal ends of focal adhesions, regions presumably undergoing disassembly. Serra-Pages et al. (1995) proposed that LAR and LIP1 may regulate disassembly of focal adhesions and help orchestrate cell-matrix interactions.
Using a yeast interaction-trap assay, Serra-Pages et al. (1998) showed that liprin-alpha-1 interacted with liprin-beta-1 and -beta-2 (PPFIBP2; 603142). Liprin-alpha-1 and -beta-1 colocalized predominantly to the plasma membrane of transfected COS cells.
Interaction with the multi-PDZ protein GRIP (GRIP1; 604597) is required for the synaptic targeting of AMPA receptors (see GRIA1; 138248). Using yeast 2-hybrid analysis of a rat brain cDNA library, Wyszynski et al. (2002) showed that PDZ domain-6 of Grip interacted with the C termini of the liprin-alpha proteins. The liprin-alpha proteins associated with pre- and postsynaptic structures in rat brain and in cultured rat hippocampal neurons. Overexpression of the liprin-alpha-1A splice variant (i.e., LIP1A), which lacks the C-terminal GRIP-binding site, selectively disrupted surface expression and synaptic clustering of AMPA receptors in cultured neurons.
Serra-Pages et al. (2005) stated that all liprin-alpha family members bind, via their LH regions, to LAR and to the related phosphatases PTP-delta (PTPRD; 601598) and PTP-sigma (PTPRS; 601576). They showed that endogenous LAR bound phosphorylated liprin-alpha-1 in a human breast cancer cell line. Liprin-alpha-1 with a mutant LH region that was unable to be phosphorylated did not bind to LAR in coprecipitation assays. Liprin-alpha-1 underwent autophosphorylation following expression in COS-7 or insect cells. Liprin-alpha-1 bound ATP agarose in vitro, and LH mutations that inhibited phosphorylation stabilized association of liprin-alpha-1 with ATP-agarose. Serra-Pages et al. (2005) concluded that liprin autophosphorylation regulates its association with LAR.
Hoogenraad et al. (2007) found that synaptic activity in cultured rat hippocampal neurons suppressed liprin-alpha-1 protein levels through degradation mediated by CamkII, an important sensor of synaptic activity, and by the ubiquitin-proteasome system. Proteasome activity was not essential for CamkII-dependent degradation of liprin-alpha-1 in COS-7 cells. A conserved C-terminal region containing potential CamkII phosphorylation sites and a PEST motif was essential for CamkII-dependent degradation of rat liprin-alpha-1. Overexpression of a liprin-alpha-1 mutant lacking this region in rat hippocampal neurons impaired dendrite arborization, reduced spine and synapse number, and inhibited dendritic targeting of Lar.
Gross (2022) mapped the PPFIA1 gene to chromosome 11q13.3 based on an alignment of the PPFIA1 sequence (GenBank BC034046) with the genomic sequence (GRCh38).
Gross, M. B. Personal Communication. Baltimore, Md. 9/2/2022.
Hoogenraad, C. C., Feliu-Mojer, M. I., Spangler, S. A., Milstein, A. D., Dunah, A. W., Hung, A. Y., Sheng, M. Liprin-alpha-1 degradation by calcium/calmodulin-dependent protein kinase II regulates LAR receptor tyrosine phosphatase distribution and dendrite development. Dev. Cell 12: 587-602, 2007. [PubMed: 17419996] [Full Text: https://doi.org/10.1016/j.devcel.2007.02.006]
Serra-Pages, C., Kedersha, N. L., Fazikas, L., Medley, Q., Debant, A., Streuli, M. The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions. EMBO J. 14: 2827-2838, 1995. [PubMed: 7796809] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb07282.x]
Serra-Pages, C., Medley, Q. G., Tang, M., Hart, A., Streuli, M. Liprins, a family of LAR transmembrane protein-tyrosine phosphatase-interacting proteins. J. Biol. Chem. 273: 15611-15620, 1998. [PubMed: 9624153] [Full Text: https://doi.org/10.1074/jbc.273.25.15611]
Serra-Pages, C., Streuli, M., Medley, Q. G. Liprin phosphorylation regulates binding to LAR: evidence for liprin autophosphorylation. Biochemistry 44: 15715-15724, 2005. [PubMed: 16313174] [Full Text: https://doi.org/10.1021/bi051434f]
Wyszynski, M., Kim, E., Dunah, A. W., Passafaro, M., Valtschanoff, J. G., Serra-Pages, C., Streuli, M., Weinberg, R. J., Sheng, M. Interaction between GRIP and liprin-alpha/SYD2 is required for AMPA receptor targeting. Neuron 34: 39-52, 2002. [PubMed: 11931740] [Full Text: https://doi.org/10.1016/s0896-6273(02)00640-2]