Intracellular pH modulation of ADF/cofilin proteins

Bernstein, Ben C.; Painter, W. B.; Chen, Hui; Minamide, Laurie S.; Abe, Hiroshi; Bamburg, James R.

doi:10.1002/1097-0169(200012)47:4<319::aid-cm6>3.0.co;2-i

Cited by 123 publications

(94 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A/C proteins show a higher depolymerizing activity at pH 8 compared with pH 6.5; the extent of pH sensitivity is much greater for vertebrate proteins than other eukaryotes (see "Discussion"). Although the physiological significance of this remains uncertain, pH-dependent effects have been demonstrated in Swiss 3T3 cells consistent with pH-sensitive regulation in vivo (8).…”

mentioning

confidence: 85%

Solution Structure of Human Cofilin

Pope

Zierler-Gould

Kühne

et al. 2004

Journal of Biological Chemistry

128

View full text Add to dashboard Cite

Human actin-depolymerizing factor (ADF) and cofilin are pH-sensitive, actin-depolymerizing proteins. Although 72% identical in sequence, ADF has a much higher depolymerizing activity than cofilin at pH 8. To understand this, we solved the structure of human cofilin using nuclear magnetic resonance and compared it with human ADF. Important sequence differences between vertebrate ADF/cofilins were correlated with unique structural determinants in the F-actin-binding site to account for differences in biochemical activities of the two proteins. Cofilin has a short ␤-strand at the C terminus, not found in ADF, which packs against strands ␤3/␤4, changing the environment around Lys 96 , a residue essential for F-actin binding. A salt bridge involving His 133 and Asp 98 (Glu 98 in ADF) may explain the pH sensitivity of human cofilin and ADF; these two residues are fully conserved in vertebrate ADF/cofilins. Chemical shift perturbations identified residues that (i) differ in their chemical environments between wild type cofilin and mutants S3D, which has greatly reduced G-actin binding, and K96Q, which does not bind F-actin; (ii) are affected when G-actin binds cofilin; and (iii) are affected by pH change from 6 to 8. Many residues affected by G-actin binding also show perturbation in the mutants or in response to pH. Our evidence suggests the involvement of residues 133-138 of strand ␤5 in all of the activities examined. Because residues in ␤5 are perturbed by mutations that affect both G-actin and Factin binding, this strand forms a "boundary" or "bridge" between the proposed F-and G-actin-binding sites.

show abstract

mentioning

confidence: 85%

Solution Structure of Human Cofilin

Pope

Zierler-Gould

Kühne

et al. 2004

Journal of Biological Chemistry

128

View full text Add to dashboard Cite

show abstract

“…Both N-and C-terminal GFP (Tsien, 1998) fusions with ADFs/cofilins have been used to visualize their interactions with the actin cytoskeleton (Aizawa et al, 1997;Bernstein et al, 2000;Dong et al, 2001a). In initial characterizations, Nor C-terminal GFP fusions with NtADF1 showed very similar labeling patterns in elongating pollen tubes, so we relied on the N-terminal fusion protein GFP-NtADF1 to examine the localization pattern of NtADF1 in pollen.…”

Section: Gfp-ntadf1 Associates With Dynamic Actin Cables In Elongatinmentioning

confidence: 99%

“…That the actin-depolymerizing activity of ADFs could play a critical role in maintaining the level of actin dynamics necessary for pollen tube elongation seems plausible. ADFs/cofilins from many species are known to depolymerize actin more efficiently under alkaline conditions (pH 7.7 to 8.5) (Hawkins et al, 1993;Gungabissoon et al, 1998;Maciver et al, 1998;Bernstein et al, 2000). Thus, their actin-depolymerizing ability could be regulated by subtle differences in H ϩ concentration within the cell, both spatially and temporally.…”

Section: Gfp-lily Adf Associates With An Actin Mesh In the Alkaline Bmentioning

confidence: 99%

The Regulation of Actin Organization by Actin-Depolymerizing Factor in Elongating Pollen Tubes[W]

et al. 2002

View full text Add to dashboard Cite

Pollen tube elongation is a polarized cell growth process that transports the male gametes from the stigma to the ovary for fertilization inside the ovules. Actomyosin-driven intracellular trafficking and active actin remodeling in the apical and subapical regions of pollen tubes are both important aspects of this rapid tip growth process. Actin-depolymerizing factor (ADF) and cofilin are actin binding proteins that enhance the depolymerization of microfilaments at their minus, or slow-growing, ends. A pollen-specific ADF from tobacco, NtADF1, was used to dissect the role of ADF in pollen tube growth. Overexpression of NtADF1 resulted in the reduction of fine, axially oriented actin cables in transformed pollen tubes and in the inhibition of pollen tube growth in a dose-dependent manner. Thus, the proper regulation of actin turnover by NtADF1 is critical for pollen tube growth. When expressed at a moderate level in pollen tubes elongating in in vitro cultures, green fluorescent protein (GFP)-tagged NtADF1 (GFP-NtADF1) associated predominantly with a subapical actin mesh composed of short actin filaments and with long actin cables in the shank. Similar labeling patterns were observed for GFP-NtADF1-expressing pollen tubes elongating within the pistil. A Ser-6-to-Asp conversion abolished the interaction between NtADF1 and F-actin in elongating pollen tubes and reduced its inhibitory effect on pollen tube growth significantly, suggesting that phosphorylation at Ser-6 may be a prominent regulatory mechanism for this pollen ADF. As with some ADF/cofilin, the in vitro actin-depolymerizing activity of recombinant NtADF1 was enhanced by slightly alkaline conditions. Because a pH gradient is known to exist in the apical region of elongating pollen tubes, it seems plausible that the in vivo actin-depolymerizing activity of NtADF1, and thus its contribution to actin dynamics, may be regulated spatially by differential H ؉ concentrations in the apical region of elongating pollen tubes.

show abstract

“…First, the phosphorylation of cofilin on serine 3 by LIM kinase 1 (LIMK1) and its related kinases (LIMK2, the skeletal muscle-specific kinases Nik related kinase (NRK, also known as NESK) and testicular protein kinase 1 (TESK1) and TESK2) regulates cofilin by inhibiting its actin-binding activity [19][20][21][22] ; second, the dephosphorylation of serine 3 of cofilin by phosphatase types 1, 2A and 2B, slingshot (SSH) and chronophin phosphatases results in the activation of actin binding by cofilin [23][24][25][26] . Third, actin binding by cofilin is inhibited by binding to phosphatidylinositol-4,5-bisphosphate (PIP2) 27,28 , and cofilin activity is dependent on phospho lipase Cγ (PLCγ)-mediated hydrolysis of PIP2 (REFS 29,30); and fourth, changes in pH over the physiological range (6.8-7.4) as mediated by the Na-H exchanger protein can activate the severing activity of cofilin when it is in the dephosphorylated state [31][32][33][34] . Furthermore, in an additional level of regulation, LIMKs are activated by phosphorylation by p21-activated kinase 1 (PAK1), PAK4 and Rho-dependent protein kinase (ROCK1) 31,105 , and inhibited by dephosphorylation by SSH1 (REF.…”

mentioning

confidence: 99%

The cofilin pathway in breast cancer invasion and metastasis

Wang¹,

2007

View full text Add to dashboard Cite

Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.Tumour cell motility is the hallmark of invasion and an essential step in metastasis 1,2 . The identification of molecular pathways that contribute to tumour cell motility and invasion is essential for understanding how motility is initiated in tumour cells and how the tumour microenvironment contributes to cell migration. The identification of the molecular pathways of tumour cell invasion will provide new diagnostic approaches and targets for the treatment of metastatic cancer. Recent studies using new technologies, including highdensity microarray-based expression profiling, intravital imaging and the collection of invasive tumour cells from live tumours, have started to extend the traditional model of metastasis and supply new diagnostic and therapeutic markers of metastatic disease.According to the traditional model of metastasis, metastases result from a process similar to Darwinian evolution whereby natural selection works on individual tumour cells to select © 2007 Nature Publishing Group Correspondence to: J.C. Condeeli@aecom.yu.edu. Competing interests statementThe authors declare no competing financial interests. for stable genetic changes. The cells so selected are very rare, and the metastatic cells that arise from this progressive selection of stable genetic mutations within the primary tumour cause metastasis late in tumour progression 3 . However, studies of mammary tumours in mice [4][5][6][7] , expression profiling of both whole human breast tumours 8,9 and the invasive subpopulation of tumour cells isolated from rat and mouse mammary tumours [10][11][12] suggest that the metastatic ability of breast tumours is encoded throughout the bulk of the primary tumour, involves transient changes in gene expression and is acquired at much earlier stages of tumour progression than postulated by the traditional model. These results suggest that a Darwinian-like evolution is accompanied by, and may contribute to, microenvironmentinduced transient changes in gene expression that support the invasive and metastatic phenotype. These results have led to new models where the microenvironment initiates the expression of genes that induce cell motility, invasion and metastasis 11,13 . In the 'tumour microenvironment invasion model' it is proposed that oncogenic mutations in tumour cells lead to microenvironments that are potentially encoded throughout the b...

show abstract

Intracellular pH modulation of ADF/cofilin proteins

Cited by 123 publications

References 77 publications

Solution Structure of Human Cofilin

Solution Structure of Human Cofilin

The Regulation of Actin Organization by Actin-Depolymerizing Factor in Elongating Pollen Tubes[W]

The cofilin pathway in breast cancer invasion and metastasis

Contact Info

Product

Resources

About