Disease relevance of PFN1

• Starting with CAL51, a human breast cancer cell line highly tumorigenic in nude mice, we established stable clones that express PFN1 mutants differentially defective in ligand binding [1].
• Profilin was also present in these actin-rich rocket tails, and microinjection of 10 microM (intracellular) ABM-2 peptide (GPPPPP)3 blocked vaccinia actin-based motility [2].
• Profilin interacts with the Gly-Pro-Pro-Pro-Pro-Pro sequences of vasodilator-stimulated phosphoprotein (VASP): implications for actin-based Listeria motility [3].
• VASP binds both profilin, an actin monomer-binding protein, and vinculin, a component of intercellular contacts that also binds the Shigella actin assembly protein IcsA [4].
• The PFN1 expression was reduced dramatically in four hepatoma cell lines compared to L02 cell line of non-tumor origin [5].

High impact information on PFN1

• In extracts and host cells, profilin is localized to the back half of the surface of motile L. monocytogenes, the site of actin filament assembly in the tail [6].
• How profilin promotes actin filament assembly in the presence of thymosin beta 4 [7].
• The movement is more effective when profilin, alpha-actinin and VASP (for Listeria) are also included [8].
• Proteins that bind to the barbed end, including capping protein, the gelsolin super-family, tensin, and profilin are discussed, as are proteins that bind to the pointed end, including tropomodulin and spectrin/band 4 [9].
• There is evidence that the polymerization of actin takes place at the plasma membrane, and that profilactin (profilin/actin complex), the unpolymerized form of actin found in extracts of many non-muscle cells, serves as the immediate precursor [10].

Chemical compound and disease context of PFN1

• Coincubation of chymase-rich BR mastocytoma cells with Ala-Ala-Pro-Phe-chloromethylketone (a chymase inhibitor) blocks profilin cleavage, which does not occur in degranulated HMC-1 mast cells, which are rich in tryptase, but chymase deficient [11].
• With use of immunoblotting,.serum IgE from 25 patients displaying type I allergic reactions to tree pollens and intolerance to hazelnuts (group I) bound to the 17 kd major hazel pollen allergen Cor a I (100%) and to the 14 kd hazel pollen profilin (16%) [12].
• CONCLUSION: In clinical settings in which laboratory investigations are not easily accessible, allergy to melon, watermelon, citrus fruits, tomato, and banana can be used as a marker of profilin hypersensitivity once a sensitization to natural rubber latex and lipid transfer protein is ruled out [13].

Biological context of PFN1

• We conclude that the actin binding site on profilin is instrumental for normal differentiation of human epithelia and the tumor suppressor function of PFN1 [1].
• The importance of PFN1 for human tissue differentiation has been demonstrated by the findings that human cancer cells, expressing conspicuously low PFN1 levels, adopt a nontumorigenic phenotype upon raising their PFN1 level [1].
• Profilin IIb appears to be a minor form, and its expression is restricted to a limited number of tissues, indicating that the alternative splicing is tightly regulated [14].
• VASP contains a central proline-rich sequence which recruits the G-actin binding protein profilin [15].
• Transfection of PFN1 cDNA into CAL51 cells raised the profilin 1 level, had a prominent effect on cell growth, cytoskeletal organization and spreading, and suppressed tumorigenicity of the stable, PFN1-overexpressing cell clones in nude mice [16].

Anatomical context of PFN1

• Profilin 1 (PFN1) is a regulator of the microfilament system and is involved in various signaling pathways [1].
• We find that profilin contributes in several ways to Cdc42-induced nucleation of actin filaments in high speed supernatant of lysed neutrophils [17].
• VASP functions as a binding intermediate between profilin and focal adhesion proteins [15].
• Although amino acid sequence analysis and RNase protection analysis suggest a single profilin isoform in mammalian cells, Southern blot analysis of human and somatic cell hybrid DNA indicates several loci in the human genome which hybridize with the profilin cDNA [18].
• We demonstrate the presence of profilin in Nck precipitates suggesting that Nck may couple extracellular signals to the cytoskeleton via its interaction with WIP and profilin [19].

Associations of PFN1 with chemical compounds

• Humans express a basic (I) and an acidic (II) isoform of profilin which exhibit different affinities for peptides and proteins rich in proline residues [20].
• Profilin I and profilin II have similar affinities for PtdIns(4,5)P2 and poly(L-proline), and both accelerate nucleotide exchange on monomeric actin to the same extent [21].
• In Acanthamoeba, the two isoforms of profilin may have specialized functions on the basis of their identical (approximately 10 microM) affinities for actin monomers and different affinities for PIP2 [22].
• In light of recent work implicating profilin from human platelets as a possible regulator of both cytoskeletal dynamics and inositol phospholipid-mediated signaling, we have further characterized the interaction of platelet profilin and the two isoforms of Acanthamoeba profilin with inositol phospholipids [22].
• Characterization of renatured profilin purified by urea elution from poly-L-proline agarose columns [23].
• The Y6D mutation reduces the affinity of human profilin-I for poly-l-proline by 1000-fold, but overexpression of Y6D profilin in fission yeast is lethal [24].

Physical interactions of PFN1

• Recent studies have revealed that profilin interacts with VASP, Mena, Bnilp, Bnrlp, and mDia, all of which have the proline-rich domain [25].
• Like SH3 domains, profilin has a surface-exposed aromatic patch which binds to proline-rich peptides [20].
• Interestingly, profilin competes with ActA for binding of Arp2/3, but actophorin (cofilin) does not [26].
• RIAM also interacts with Profilin and Ena/VASP proteins, molecules that regulate actin dynamics [27].
• To our knowledge, AF-6 is the only integral component in cell-cell junctions discovered thus far that interacts with profilin and thus could modulate actin modeling proximal to adhesion complexes [28].

Co-localisations of PFN1

• Binding to the Golgi was verified by indirect immunofluorescence in MT-1 cells showing that a fraction of profilin I colocalizes with TGN38, a marker of the trans-Golgi network (TGN) [29].

Regulatory relationships of PFN1

• Profilin enhances Cdc42-induced nucleation of actin polymerization [17].
• These data suggest that under conditions present in intact cells, profilin enhances nucleation by activated Arp2/3 complex [17].
• This mutant profilin I suppresses actin polymerization in microspike formation induced by N-WASP, the essential factor in microspike formation [30].
• Notably, the antibody displaces a fraction of the Golgi-bound dynamin II indicating that profilin I may indirectly promote vesicle formation by supporting the binding of dynamin II to the Golgi membrane [29].
• Recombinant plant (birch) profilin was analyzed for its ability to promote actin polymerization from the actin:thymosin beta4 and beta9 complex [31].

Other interactions of PFN1

• Unmasking of this site serves as a molecular switch that initiates assembly of an actin-based motility complex containing VASP and profilin [32].
• Potential structural differences of profilin I and profilin II that might explain the difference in actin binding are discussed [21].
• Profilin catalyzes exchange of ADP for ATP, recycling actin back to a pool of unpolymerized monomers bound to profilin and thymosin-beta 4 that is poised for rapid elongation of new barbed ends [33].
• The isolated COOH-terminal domain of N-WASP containing a verprolin-homology region, a cofilin-homology sequence, and an acidic terminal segment (VCA) interacts with G-actin in a unique profilin-like functional fashion [34].
• Indeed, we show that extracellular S100A4 treatments decrease both the amount of polymerized F-actin and the levels of expression of RhoA, mDia and profilin [35].

Analytical, diagnostic and therapeutic context of PFN1

• Western blotting and whole-mount in situ hybridization show that, in contrast to the expression of profilin I, the expression level of profilin IIa is developmentally regulated [14].
• In this paper, we describe the molecular cloning and characterization of a novel form of profilin, termed profilin-3, from rat kidney using a PCR-based procedure for isolating tissue-specific genes [36].
• We now report that fluorescence titration showed that GP5GP5GP5 peptide binds to profilin (KD of 84 microM), and the peptide weakly inhibits exchange of actin-bound nucleotide in the absence or presence of profilin [3].
• We present evidence that native profilin can be purified from cellular extracts of Acanthamoeba, Dictyostelium, and human platelets by affinity chromatography on poly-L-proline agarose [23].
• The PFN1 expression was also examined in 4 cases of primary hepatocarcinoma tissues by Western blot and 30 cases by tissues microarray [5].

References