Profilin gene, PFN1, Profilin1

 

NCBI Gene Summary for PFN1 Gene

• This gene encodes a member of the profilin family of small actin-binding proteins. The encoded protein plays an important role in actin dynamics by regulating actin polymerization in response to extracellular signals. Deletion of this gene is associated with Miller-Dieker syndrome, and the encoded protein may also play a role in Huntington disease. Multiple pseudogenes of this gene are located on chromosome 1. [provided by RefSeq, Jul 2012]

GeneCards Summary for PFN1 Gene

PFN1 (Profilin 1) is a Protein Coding gene. Diseases associated with PFN1 include Amyotrophic Lateral Sclerosis 18 and Frontotemporal Dementia And/Or Amyotrophic Lateral Sclerosis 7. Among its related pathways are Response to elevated platelet cytosolic Ca2+ and Nervous system development. Gene Ontology (GO) annotations related to this gene include RNA binding and actin binding. An important paralog of this gene is PFN2.

UniProtKB/Swiss-Prot Summary for PFN1 Gene

Binds to actin and affects the structure of the cytoskeleton. At high concentrations, profilin prevents the polymerization of actin, whereas it enhances it at low concentrations. By binding to PIP2, it inhibits the formation of IP3 and DG. Inhibits androgen receptor (AR) and HTT aggregation and binding of G-actin is essential for its inhibition of AR. ( PROF1_HUMAN,P07737 )

Protein attributes for PFN1 Gene

Size: 140 amino acids

Molecular mass: 15054 Da

Quaternary structure:

• Found in a complex with XPO6, Ran, ACTB and PFN1 (PubMed:14592989).
  Interacts with ACTB (PubMed:10411937).
  Interacts with VASP (PubMed:17914456, 18689676).
  Interacts with HTT (PubMed:18573880). huntingtin
  Interacts with SH3BGRL (PubMed:34331014).
  Occurs in many kinds of cells as a complex with monomeric actin in a 1:1 ratio (PubMed:17914456, 18689676).
  Interacts with ACTMAP (PubMed:36173861).

Aktiinin osuus  Tumassa: Kuva: Profiliinin  paikka aktiinin kuljetuksessa tumasta ulos.    https://pmc.ncbi.nlm.nih.gov/articles/PMC3632617/figure/F1/

  Thus, the amount of actin in the cell nucleus can drastically increase or decrease in a wide range of cell types but also in species from different taxonomic phyla. This implies that nuclear localization of actin is tightly regulated, and that this regulation is an evolutionary conserved feature. However, the mechanisms governing the interconnection between nuclear and cytoplasmic actin pools have remained largely unclear. This question, which is central in order to perceive the full range of the potential functions of nuclear actin in cells, has been tackled by our lab in a recent publication in the journal PNAS.Citation⁹

  The size of actin, 43 kDa, is at the border of the size exclusion limit for passive diffusion through the nuclear pore complex and this fact has clearly complicated the analysis of nuclear import mechanism for actin. On the contrary, two active nuclear export pathways for actin, dependent on either Crm1¹⁰ or exportin 6,¹¹ have been described in the literature.

.. In fact, one third of nuclear actin is exchanged every 100 sec. This demonstrates that there is extensive and dynamic communication between the cytoplasmic and nuclear actin pools. Interestingly, the availability of actin monomers seems to limit the nuclear transport rate in both directions. This implies that both the extent of actin polymerization or binding to different complexes may modulate nuclear actin levels by restricting the availability of transport-competent actin monomers. By using a combination of imaging approaches and RNA interference (RNAi), we further showed that inhibition of Crm1 does not affect nuclear export of actin. Hence, the earlier study linking Crm1 to actin export could be due to indirect effects on nuclear export of many actin-binding proteins or the actin probes used in this study.Citation¹⁰ Instead, we found that exportin 6 mediated the export of actin both in the murine fibroblastic cell line NIH 3T3 and the Drosophila cell line S2R+, demonstrating that this export mechanism is largely shared among eukaryotes.Citation⁹ This data therefore confirms and extends the previous results implicating exportin 6 as the major nuclear export receptor for actin.Citation^11-Citation¹³

 ...hat nuclear import of actin is an active process, because passive diffusion would have been sensitive to the size of the construct as demonstrated for GFP and 2GFP. This data was further corroborated by the finding that importin 9, an importin-β family member, is required to maintain nuclear actin levels. As importin 9 interacts both with actin and cofilin in a co-immunoprecipitation experiment, we hypothesize that actin enters the nucleus as a complex with importin 9 and cofilin.Combined, this data reveals the regulatory points that the cell can use to modulate its nuclear actin levels. These mechanisms include the concentration or activity of importin 9 and exportin 6 transport proteins, the availability of the transport cofactors cofilin and profilin and the availability of free actin monomers ().Citation⁹

 Profiliini.aktiini- kompleksi on suurin polymerisoitumiskykyinen  aktiiniaines solussa: Siinä muodossa aktiini ei polymerisoidu.

 https://pubmed.ncbi.nlm.nih.gov/17914456/  Cells sustain high rates of actin filament elongation by maintaining a large pool of actin monomers above the critical concentration for polymerization. Profilin-actin complexes constitute the largest fraction of polymerization-competent actin monomers. Filament elongation factors such as Ena/VASP and formin catalyze the transition of profilin-actin from the cellular pool onto the barbed end of growing filaments. The molecular bases of this process are poorly understood. Here we present structural and energetic evidence for two consecutive steps of the elongation mechanism: the recruitment of profilin-actin by the last poly-Pro segment of vasodilator-stimulated phosphoprotein (VASP) and the binding of profilin-actin simultaneously to this poly-Pro and to the G-actin-binding (GAB) domain of VASP. The actin monomer bound at the GAB domain is proposed to be in position to join the barbed end of the growing filament concurrently with the release of profilin.

 

myös polyglutamiini kilpailee profiliinista.

https://pubmed.ncbi.nlm.nih.gov/18573880/ 

Y-27632, an inhibitor of the Rho-associated kinase ROCK, is a therapeutic lead for Huntington disease (HD). The downstream targets that mediate its inhibitory effects on huntingtin (Htt) aggregation and toxicity are unknown. We have identified profilin, a small actin-binding factor that also interacts with Htt, as being a direct target of the ROCK1 isoform. The overexpression of profilin reduces the aggregation of polyglutamine-expanded Htt and androgen receptor (AR) peptides. This requires profilin's G-actin binding activity and its direct interaction with Htt, which are both inhibited by the ROCK1-mediated phosphorylation of profilin at Ser-137. Y-27632 blocks the phosphorylation of profilin in HEK293 cells and primary neurons, which maintains profilin in an active state. The knockdown of profilin blocks the inhibitory effect of Y-27632 on both AR and Htt aggregation. A signaling pathway from ROCK1 to profilin thus controls polyglutamine protein aggregation and is targeted by a promising therapeutic lead for HD. 

 

 PTEN ja PROFILINGEENI     PFN1  alassäätyneet   syöpämetastaasissa  

 Abstract

Metastatic recurrence is still a major challenge in breast cancer treatment, but the underlying mechanisms remain unclear. Here, we report that a small adaptor protein, SH3BGRL, is upregulated in the majority of breast cancer patients, especially elevated in those with metastatic relapse, indicating it as a marker for the poor prognosis of breast cancer. Physiologically, SH3BGRL can multifunctionally promote breast cancer cell tumorigenicity, migration, invasiveness, and efficient lung colonization in nude mice. Mechanistically, SH3BGRL downregulates the acting-binding protein profilin 1 (PFN1) by accelerating the translation of the PFN1 E3 ligase, STUB1 via SH3BGRL interaction with ribosomal proteins, or/and enhancing the interaction of PFN1 with STUB1 to accelerate PFN1 degradation. 

Loss of PFN1 consequently contributes to downstream multiple activations of AKT, NF-_kB, and WNT signaling pathways. In contrast, the forced expression of compensatory PFN1 in SH3BGRL-high cells efficiently neutralizes SH3BGRL-induced metastasis and tumorigenesis with PTEN upregulation and PI3K-AKT signaling inactivation. Clinical analysis validates that SH3BGRL expression is negatively correlated with PFN1 and PTEN levels, but positively to the activations of AKT, NF-_kB, and WNT signaling pathways in breast patient tissues. Our results thus suggest that SH3BGRL is a valuable prognostic factor and a potential therapeutic target for preventing breast cancer progression and metastasis.

 

 Tässä yhteydessä pitäisi katsoa myös  cofilin proteiinin osuus.