Systematic Identification and Quantification of Substrate Specificity Determinants in Human Protein Kinases
Protein kinases participate in a myriad of cellular
processes of major biomedical interest. The in vivo substrate
specificity of these enzymes is a process determined by several
factors, and despite several years of research on the topic, is still
far from being totally understood. In the present work, we have
quantified the contributions to the kinase substrate specificity of
i) the phosphorylation sites and their surrounding residues in the
sequence and of ii) the association of kinases to adaptor or scaffold
proteins. We have used position-specific scoring matrices (PSSMs),
to represent the stretches of sequences phosphorylated by 93 families
of kinases. We have found negative correlations between the number
of sequences from which a PSSM is generated and the statistical
significance and the performance of that PSSM. Using a subset
of 22 statistically significant PSSMs, we have identified specificity
determinant residues (SDRs) for 86% of the corresponding kinase
families. Our results suggest that different SDRs can function as
positive or negative elements of substrate recognition by the different
families of kinases. Additionally, we have found that human proteins
with known function as adaptors or scaffolds (kAS) tend to interact
with a significantly large fraction of the substrates of the kinases to
which they associate. Based on this characteristic we have identified
a set of 279 potential adaptors/scaffolds (pAS) for human kinases,
which is enriched in Pfam domains and functional terms tightly
related to the proposed function. Moreover, our results show that
for 74.6% of the kinase–pAS association found, the pAS colocalize
with the substrates of the kinases they are associated to. Finally, we
have found evidence suggesting that the association of kinases to
adaptors and scaffolds, may contribute significantly to diminish the
in vivo substrate crossed-specificity of protein kinases. In general, our
results indicate the relevance of several SDRs for both the positive
and negative selection of phosphorylation sites by kinase families and
also suggest that the association of kinases to pAS proteins may be
an important factor for the localization of the enzymes with their set
of substrates.
[1] P. Cohen, "The origins of protein phosphorylation.” Nature cell biology,
vol. 4, no. 5, pp. E127–30, May 2002.
[2] S. Arena, S. Benvenuti, and a. Bardelli, "Genetic analysis of the kinome
and phosphatome in cancer.” Cellular and molecular life sciences :
CMLS, vol. 62, no. 18, pp. 2092–9, Sep. 2005.
[3] A. Forrest, T. Ravasi, D. Taylor, T. Huber, D. Hume, and S. Grimmond,
"Phosphoregulators: protein kinases and protein phosphatases of mouse,”
Genome research, vol. 13, no. 6b, p. 1443, 2003.
[4] G. Manning, D. B. Whyte, R. Martinez, T. Hunter, and S. Sudarsanam,
"The protein kinase complement of the human genome.” Science (New
York, N.Y.), vol. 298, no. 5600, pp. 1912–34, Dec. 2002.
[5] A. Torkamani, G. Verkhivker, and N. J. Schork, "Cancer driver mutations
in protein kinase genes.” Cancer letters, vol. 281, no. 2, pp. 117–27,
Aug. 2009.
[6] P. Cohen, "The role of protein phosphorylation in human health and
disease,” Eur J Biochem., vol. 268, no. 19, pp. 5001–5010, 2001.
[7] L. R. Pearce, D. Komander, and D. R. Alessi, "The nuts and bolts of
AGC protein kinases.” Nature reviews. Molecular cell biology, vol. 11,
no. 1, pp. 9–22, Jan. 2010.
[8] K. Deshmukh, K. Anamika, and N. Srinivasan, "Evolution of domain
combinations in protein kinases and its implications for functional
diversity.” Progress in biophysics and molecular biology, vol. 102, no. 1,
pp. 1–15, Jan. 2010.
[9] J. Alexander, D. Lim, B. a. Joughin, B. Hegemann, J. R. a. Hutchins,
T. Ehrenberger, F. Ivins, F. Sessa, O. Hudecz, E. a. Nigg, A. M.
Fry, A. Musacchio, P. T. Stukenberg, K. Mechtler, J.-M. Peters, S. J.
Smerdon, and M. B. Yaffe, "Spatial exclusivity combined with positive
and negative selection of phosphorylation motifs is the basis for
context-dependent mitotic signaling.” Science signaling, vol. 4, no. 179,
p. ra42, Jan. 2011.
[10] A. N. Kettenbach, D. K. Schweppe, B. K. Faherty, D. Pechenick,
A. a. Pletnev, and S. a. Gerber, "Quantitative phosphoproteomics
identifies substrates and functional modules of aurora and polo-like
kinase activities in mitotic cells.” Science signaling, vol. 4, no. 179,
p. rs5, Jan. 2011.
[11] J. Ptacek, G. Devgan, G. Michaud, H. Zhu, X. Zhu, J. Fasolo, H. Guo,
G. Jona, A. Breitkreutz, R. Sopko, R. R. McCartney, M. C. Schmidt,
N. Rachidi, S.-J. Lee, A. S. Mah, L. Meng, M. J. R. Stark, D. F. Stern,
C. De Virgilio, M. Tyers, B. Andrews, M. Gerstein, B. Schweitzer, P. F.
Predki, and M. Snyder, "Global analysis of protein phosphorylation in
yeast.” Nature, vol. 438, no. 7068, pp. 679–84, Dec. 2005.
[12] J. A. Ubersax and J. E. Ferrell, "Mechanisms of specificity in protein
phosphorylation.” Nature reviews. Molecular cell biology, vol. 8, no. 7,
pp. 530–41, Jul. 2007.
[13] B. Kobe, T. Kampmann, and J. K. Forwood, "Substrate specificity of
protein kinases and computational prediction of substrates,” Biochimica
et biophysica acta, vol. 1754, pp. 200 – 209, 2005.
[14] H. Zhu, J. F. Klemic, S. Chang, P. Bertone, a. Casamayor, K. G. Klemic,
D. Smith, M. Gerstein, M. a. Reed, and M. Snyder, "Analysis of yeast
protein kinases using protein chips.” Nature genetics, vol. 26, no. 3, pp.
283–9, Nov. 2000.
[15] J. V. Olsen, B. Blagoev, F. Gnad, B. Macek, C. Kumar, P. Mortensen, and
M. Mann, "Global, in vivo, and site-specific phosphorylation dynamics
in signaling networks.” Cell, vol. 127, no. 3, pp. 635–48, Nov. 2006.
[16] J. Mok, P. M. Kim, H. Y. K. Lam, S. Piccirillo, X. Zhou, G. R. Jeschke,
D. L. Sheridan, S. a. Parker, V. Desai, M. Jwa, E. Cameroni, H. Niu,
M. Good, A. Remenyi, J.-L. N. Ma, Y.-J. Sheu, H. E. Sassi, R. Sopko,
C. S. M. Chan, C. De Virgilio, N. M. Hollingsworth, W. a. Lim, D. F.
Stern, B. Stillman, B. J. Andrews, M. B. Gerstein, M. Snyder, and
B. E. Turk, "Deciphering protein kinase specificity through large-scale
analysis of yeast phosphorylation site motifs.” Science signaling, vol. 3,
no. 109, p. ra12, Jan. 2010.
[17] B. Hegemann, J. R. a. Hutchins, O. Hudecz, M. Novatchkova,
J. Rameseder, M. M. Sykora, S. Liu, M. Mazanek, P. Lenart, J.-K.
Heriche, I. Poser, N. Kraut, a. a. Hyman, M. B. Yaffe, K. Mechtler, and
J.-M. Peters, "Systematic Phosphorylation Analysis of Human Mitotic
Protein Complexes,” Science Signaling, vol. 4, no. 198, pp. rs12–rs12,
Nov. 2011.
[18] A. Kreegipuu, N. Blom, S. Brunak, and J. Ja, "Statistical analysis of
protein kinase specificity determinants,” FEBS letters, vol. 430, pp.
45–50, 1998.
[19] R. H. Newman, J. Hu, H.-S. Rho, Z. Xie, C. Woodard, J. Neiswinger,
C. Cooper, M. Shirley, H. M. Clark, S. Hu, W. Hwang, J. Seop Jeong,
G. Wu, J. Lin, X. Gao, Q. Ni, R. Goel, S. Xia, H. Ji, K. N. Dalby,
M. J. Birnbaum, P. a. Cole, S. Knapp, A. G. Ryazanov, D. J. Zack,
S. Blackshaw, T. Pawson, A.-C. Gingras, S. Desiderio, A. Pandey,
B. E. Turk, J. Zhang, H. Zhu, and J. Qian, "Construction of human
activity-based phosphorylation networks,” Molecular Systems Biology,
vol. 9, no. 655, pp. 1–12, Apr. 2013.
[20] G. Z. Hertz and G. D. Stormo, "Identifying DNA and protein
patterns with statistically significant alignments of multiple sequences.”
Bioinformatics (Oxford, England), vol. 15, no. 7-8, pp. 563–77, 1999.
[21] J. C. Obenauer, "Scansite 2.0: proteome-wide prediction of cell signaling
interactions using short sequence motifs,” Nucleic Acids Research,
vol. 31, no. 13, pp. 3635–3641, Jul. 2003.
[22] N. F. W. Saunders, R. I. Brinkworth, T. Huber, B. E. Kemp, and
B. Kobe, "Predikin and PredikinDB : a computational framework for
the prediction of protein kinase peptide specificity and an associated
database of phosphorylation sites,” BMC Bioinformatics, vol. 11, pp.
1–11, 2008.
[23] N. Blom, T. Sicheritz-Pont´en, R. Gupta, S. Gammeltoft, and S. r. Brunak,
"Prediction of post-translational glycosylation and phosphorylation of
proteins from the amino acid sequence.” Proteomics, vol. 4, no. 6, pp.
1633–49, Jun. 2004.
[24] M. C. Good, J. G. Zalatan, and W. a. Lim, "Scaffold Proteins: Hubs
for Controlling the Flow of Cellular Information,” Science, vol. 332, no.
6030, pp. 680–686, May 2011.
[25] C. D. White, M. D. Brown, and D. B. Sacks, "IQGAPs in cancer: a
family of scaffold proteins underlying tumorigenesis.” FEBS letters, vol.
583, no. 12, pp. 1817–24, Jun. 2009.
[26] H. Zhang, A. Photiou, G. Arnhild, J. Stebbing, and G. Giamas, "The
role of pseudokinases in cancer.” Cellular signalling, vol. 24, no. 6, pp.
1173–1184, Feb. 2012.
[27] A. S. Shaw and E. L. Filbert, "Scaffold proteins and immune-cell
signalling.” Nature reviews. Immunology, vol. 9, no. 1, pp. 47–56, Jan.
2009.
[28] A. Alexa, J. Varga, and A. Rem´enyi, "Scaffolds are ’active’ regulators of
signaling modules.” The FEBS journal, vol. 277, no. 21, pp. 4376–82,
Nov. 2010.
[29] M. Colledge and J. D. Scott, "AKAPs: from structure to function.”
Trends in cell biology, vol. 9, no. 6, pp. 216–21, Jun. 1999.
[30] M. M. McKay, D. a. Ritt, and D. K. Morrison, "Signaling dynamics of
the KSR1 scaffold complex.” Proceedings of the National Academy of
Sciences of the United States of America, vol. 106, no. 27, pp. 11 022–7,
Jul. 2009.
[31] F. Ram´ırez and M. Albrecht, "Finding scaffold proteins in interactomes.”
Trends in cell biology, vol. 20, no. 1, pp. 2–4, Jan. 2010.
[32] D. F. Brennan, A. C. Dar, N. T. Hertz, W. C. H. Chao, A. L. Burlingame,
K. M. Shokat, and D. Barford, "A Raf-induced allosteric transition of
KSR stimulates phosphorylation of MEK.” Nature, vol. 472, no. 7343,
pp. 366–9, Apr. 2011.
[33] W. G. Cance, E. Kurenova, T. Marlowe, and V. Golubovskaya,
"Disrupting the Scaffold to Improve Focal Adhesion Kinase-Targeted
Cancer Therapeutics,” Science Signaling, vol. 6, no. 268, pp. pe10–pe10,
Mar. 2013.
[34] T. S. Keshava Prasad, R. Goel, K. Kandasamy, S. Keerthikumar,
S. Kumar, S. Mathivanan, D. Telikicherla, R. Raju, B. Shafreen,
A. Venugopal, L. Balakrishnan, A. Marimuthu, S. Banerjee, D. S.
Somanathan, A. Sebastian, S. Rani, S. Ray, C. J. Harrys Kishore,
S. Kanth, M. Ahmed, M. K. Kashyap, R. Mohmood, Y. L.
Ramachandra, V. Krishna, B. A. Rahiman, S. Mohan, P. Ranganathan,
S. Ramabadran, R. Chaerkady, and A. Pandey, "Human Protein
Reference Database–2009 update.” Nucleic acids research, vol. 37, no.
Database issue, pp. D767–72, Jan. 2009.
[35] P. V. Hornbeck, I. Chabra, J. M. Kornhauser, E. Skrzypek, and B. Zhang,
"PhosphoSite: A bioinformatics resource dedicated to physiological
protein phosphorylation.” Proteomics, vol. 4, no. 6, pp. 1551–61, Jun.
2004.
[36] H. Dinkel, C. Chica, A. Via, C. M. Gould, L. J. Jensen, T. J.
Gibson, and F. Diella, "Phospho.ELM: a database of phosphorylation
sites–update 2011.” Nucleic acids research, vol. 39, no. November 2010,
pp. 261–267, Nov. 2010.
[37] J. M. Claverie and S. Audic, "The statistical significance of
nucleotide position-weight matrix matches.” Computer applications in
the biosciences : CABIOS, vol. 12, no. 5, pp. 431–9, Oct 1996.
[38] G. D. Stormo, "DNA binding sites: representation and discovery.”
Bioinformatics (Oxford, England), vol. 16, no. 1, pp. 16–23, Jan. 2000.
[39] R. Mosca, A. C´eol, and P. Aloy, "Interactome3D: adding structural
details to protein networks.” Nature methods, vol. 10, no. 1, pp. 47–53,
Dec. 2013.
[40] G. Badis, M. F. Berger, A. a. Philippakis, S. Talukder, A. R. Gehrke,
S. a. Jaeger, E. T. Chan, G. Metzler, A. Vedenko, X. Chen, H. Kuznetsov,
C.-F. Wang, D. Coburn, D. E. Newburger, Q. Morris, T. R. Hughes,
and M. L. Bulyk, "Diversity and complexity in DNA recognition by
transcription factors.” Science (New York, N.Y.), vol. 324, no. 5935, pp.
1720–3, Jun. 2009.
[41] D. Matenia and E.-M. Mandelkow, "The tau of MARK: a polarized view
of the cytoskeleton.” Trends in biochemical sciences, vol. 34, no. 7, pp.
332–42, Jul. 2009.
[42] A. Alonso, T. Zaidi, M. Novak, I. Grundke-Iqbal, and K. Iqbal,
"Hyperphosphorylation induces self-assembly of tau into tangles of
paired helical filaments/straight filaments.” Proceedings of the National
Academy of Sciences of the United States of America, vol. 98, no. 12,
pp. 6923–8, Jun. 2001.
[43] H. Matsuzaki, A. Ichino, T. Hayashi, T. Yamamoto, and U. Kikkawa,
"Regulation of intracellular localization and transcriptional activity of
FOXO4 by protein kinase B through phosphorylation at the motif sites
conserved among the FOXO family.” Journal of biochemistry, vol. 138,
no. 4, pp. 485–91, Oct. 2005.
[44] M. Punta, P. C. Coggill, R. Y. Eberhardt, J. Mistry, J. Tate, C. Boursnell,
N. Pang, K. Forslund, G. Ceric, J. Clements, A. Heger, L. Holm, E. L. L.
Sonnhammer, S. R. Eddy, A. Bateman, and R. D. Finn, "The Pfam
protein families database.” Nucleic acids research, vol. 40, no. Database
issue, pp. D290–301, Jan. 2012.
[45] M. Ashburner, C. A. Ball, J. A. Blake, D. Botstein, H. Butler, J. M.
Cherry, A. P. Davis, K. Dolinski, S. S. Dwight, J. T. Eppig, M. A.
Harris, D. P. Hill, L. Issel-Tarver, A. Kasarskis, S. Lewis, J. C. Matese,
J. E. Richardson, M. Ringwald, G. M. Rubin, and G. Sherlock, "Gene
ontology: tool for the unification of biology. The Gene Ontology
Consortium.” Nature genetics, vol. 25, no. 1, pp. 25–9, May 2000.
[46] A. Zeke, M. Luk´acs, W. a. Lim, and A. Rem´enyi, "Scaffolds: interaction
platforms for cellular signalling circuits.” Trends in cell biology, vol. 19,
no. 8, pp. 364–74, Aug. 2009.
[47] S. Karthikeyan, T. Leung, and J. A. A. Ladias, "Structural determinants
of the Na+/H+ exchanger regulatory factor interaction with the beta 2
adrenergic and platelet-derived growth factor receptors.” The Journal of
biological chemistry, vol. 277, no. 21, pp. 18 973–8, May 2002.
[48] K. Jiang, E. Pereira, M. Maxfield, B. Russell, D. M. Goudelock, and
Y. Sanchez, "Regulation of Chk1 includes chromatin association and
14-3-3 binding following phosphorylation on Ser-345.” The Journal of
biological chemistry, vol. 278, no. 27, pp. 25 207–17, Jul. 2003.
[49] G. A. Penman, L. Leung, and I. S. N¨athke, "The adenomatous polyposis
coli protein (APC) exists in two distinct soluble complexes with different
functions.” Journal of cell science, vol. 118, no. Pt 20, pp. 4741–50, Oct.
2005.
[50] C. Reichen, S. Hansen, and A. Plckthun, "Modular peptide binding:
From a comparison of natural binders to designed armadillo repeat
proteins,” Journal of Structural Biology, vol. In press, no. 0, p.
http://dx.doi.org/10.1016/j.jsb.2013.07.012, 2013.
[51] R. Roskoski, "ERK1/2 MAP kinases: structure, function, and
regulation.” Pharmacological research : the official journal of the Italian
Pharmacological Society, vol. 66, no. 2, pp. 105–43, Aug. 2012.
[52] A. C. Lloyd, "Distinct functions for ERKs?” Journal of Biology, vol. 5,
no. 5, p. 13, Jan. 2006.
[1] P. Cohen, "The origins of protein phosphorylation.” Nature cell biology,
vol. 4, no. 5, pp. E127–30, May 2002.
[2] S. Arena, S. Benvenuti, and a. Bardelli, "Genetic analysis of the kinome
and phosphatome in cancer.” Cellular and molecular life sciences :
CMLS, vol. 62, no. 18, pp. 2092–9, Sep. 2005.
[3] A. Forrest, T. Ravasi, D. Taylor, T. Huber, D. Hume, and S. Grimmond,
"Phosphoregulators: protein kinases and protein phosphatases of mouse,”
Genome research, vol. 13, no. 6b, p. 1443, 2003.
[4] G. Manning, D. B. Whyte, R. Martinez, T. Hunter, and S. Sudarsanam,
"The protein kinase complement of the human genome.” Science (New
York, N.Y.), vol. 298, no. 5600, pp. 1912–34, Dec. 2002.
[5] A. Torkamani, G. Verkhivker, and N. J. Schork, "Cancer driver mutations
in protein kinase genes.” Cancer letters, vol. 281, no. 2, pp. 117–27,
Aug. 2009.
[6] P. Cohen, "The role of protein phosphorylation in human health and
disease,” Eur J Biochem., vol. 268, no. 19, pp. 5001–5010, 2001.
[7] L. R. Pearce, D. Komander, and D. R. Alessi, "The nuts and bolts of
AGC protein kinases.” Nature reviews. Molecular cell biology, vol. 11,
no. 1, pp. 9–22, Jan. 2010.
[8] K. Deshmukh, K. Anamika, and N. Srinivasan, "Evolution of domain
combinations in protein kinases and its implications for functional
diversity.” Progress in biophysics and molecular biology, vol. 102, no. 1,
pp. 1–15, Jan. 2010.
[9] J. Alexander, D. Lim, B. a. Joughin, B. Hegemann, J. R. a. Hutchins,
T. Ehrenberger, F. Ivins, F. Sessa, O. Hudecz, E. a. Nigg, A. M.
Fry, A. Musacchio, P. T. Stukenberg, K. Mechtler, J.-M. Peters, S. J.
Smerdon, and M. B. Yaffe, "Spatial exclusivity combined with positive
and negative selection of phosphorylation motifs is the basis for
context-dependent mitotic signaling.” Science signaling, vol. 4, no. 179,
p. ra42, Jan. 2011.
[10] A. N. Kettenbach, D. K. Schweppe, B. K. Faherty, D. Pechenick,
A. a. Pletnev, and S. a. Gerber, "Quantitative phosphoproteomics
identifies substrates and functional modules of aurora and polo-like
kinase activities in mitotic cells.” Science signaling, vol. 4, no. 179,
p. rs5, Jan. 2011.
[11] J. Ptacek, G. Devgan, G. Michaud, H. Zhu, X. Zhu, J. Fasolo, H. Guo,
G. Jona, A. Breitkreutz, R. Sopko, R. R. McCartney, M. C. Schmidt,
N. Rachidi, S.-J. Lee, A. S. Mah, L. Meng, M. J. R. Stark, D. F. Stern,
C. De Virgilio, M. Tyers, B. Andrews, M. Gerstein, B. Schweitzer, P. F.
Predki, and M. Snyder, "Global analysis of protein phosphorylation in
yeast.” Nature, vol. 438, no. 7068, pp. 679–84, Dec. 2005.
[12] J. A. Ubersax and J. E. Ferrell, "Mechanisms of specificity in protein
phosphorylation.” Nature reviews. Molecular cell biology, vol. 8, no. 7,
pp. 530–41, Jul. 2007.
[13] B. Kobe, T. Kampmann, and J. K. Forwood, "Substrate specificity of
protein kinases and computational prediction of substrates,” Biochimica
et biophysica acta, vol. 1754, pp. 200 – 209, 2005.
[14] H. Zhu, J. F. Klemic, S. Chang, P. Bertone, a. Casamayor, K. G. Klemic,
D. Smith, M. Gerstein, M. a. Reed, and M. Snyder, "Analysis of yeast
protein kinases using protein chips.” Nature genetics, vol. 26, no. 3, pp.
283–9, Nov. 2000.
[15] J. V. Olsen, B. Blagoev, F. Gnad, B. Macek, C. Kumar, P. Mortensen, and
M. Mann, "Global, in vivo, and site-specific phosphorylation dynamics
in signaling networks.” Cell, vol. 127, no. 3, pp. 635–48, Nov. 2006.
[16] J. Mok, P. M. Kim, H. Y. K. Lam, S. Piccirillo, X. Zhou, G. R. Jeschke,
D. L. Sheridan, S. a. Parker, V. Desai, M. Jwa, E. Cameroni, H. Niu,
M. Good, A. Remenyi, J.-L. N. Ma, Y.-J. Sheu, H. E. Sassi, R. Sopko,
C. S. M. Chan, C. De Virgilio, N. M. Hollingsworth, W. a. Lim, D. F.
Stern, B. Stillman, B. J. Andrews, M. B. Gerstein, M. Snyder, and
B. E. Turk, "Deciphering protein kinase specificity through large-scale
analysis of yeast phosphorylation site motifs.” Science signaling, vol. 3,
no. 109, p. ra12, Jan. 2010.
[17] B. Hegemann, J. R. a. Hutchins, O. Hudecz, M. Novatchkova,
J. Rameseder, M. M. Sykora, S. Liu, M. Mazanek, P. Lenart, J.-K.
Heriche, I. Poser, N. Kraut, a. a. Hyman, M. B. Yaffe, K. Mechtler, and
J.-M. Peters, "Systematic Phosphorylation Analysis of Human Mitotic
Protein Complexes,” Science Signaling, vol. 4, no. 198, pp. rs12–rs12,
Nov. 2011.
[18] A. Kreegipuu, N. Blom, S. Brunak, and J. Ja, "Statistical analysis of
protein kinase specificity determinants,” FEBS letters, vol. 430, pp.
45–50, 1998.
[19] R. H. Newman, J. Hu, H.-S. Rho, Z. Xie, C. Woodard, J. Neiswinger,
C. Cooper, M. Shirley, H. M. Clark, S. Hu, W. Hwang, J. Seop Jeong,
G. Wu, J. Lin, X. Gao, Q. Ni, R. Goel, S. Xia, H. Ji, K. N. Dalby,
M. J. Birnbaum, P. a. Cole, S. Knapp, A. G. Ryazanov, D. J. Zack,
S. Blackshaw, T. Pawson, A.-C. Gingras, S. Desiderio, A. Pandey,
B. E. Turk, J. Zhang, H. Zhu, and J. Qian, "Construction of human
activity-based phosphorylation networks,” Molecular Systems Biology,
vol. 9, no. 655, pp. 1–12, Apr. 2013.
[20] G. Z. Hertz and G. D. Stormo, "Identifying DNA and protein
patterns with statistically significant alignments of multiple sequences.”
Bioinformatics (Oxford, England), vol. 15, no. 7-8, pp. 563–77, 1999.
[21] J. C. Obenauer, "Scansite 2.0: proteome-wide prediction of cell signaling
interactions using short sequence motifs,” Nucleic Acids Research,
vol. 31, no. 13, pp. 3635–3641, Jul. 2003.
[22] N. F. W. Saunders, R. I. Brinkworth, T. Huber, B. E. Kemp, and
B. Kobe, "Predikin and PredikinDB : a computational framework for
the prediction of protein kinase peptide specificity and an associated
database of phosphorylation sites,” BMC Bioinformatics, vol. 11, pp.
1–11, 2008.
[23] N. Blom, T. Sicheritz-Pont´en, R. Gupta, S. Gammeltoft, and S. r. Brunak,
"Prediction of post-translational glycosylation and phosphorylation of
proteins from the amino acid sequence.” Proteomics, vol. 4, no. 6, pp.
1633–49, Jun. 2004.
[24] M. C. Good, J. G. Zalatan, and W. a. Lim, "Scaffold Proteins: Hubs
for Controlling the Flow of Cellular Information,” Science, vol. 332, no.
6030, pp. 680–686, May 2011.
[25] C. D. White, M. D. Brown, and D. B. Sacks, "IQGAPs in cancer: a
family of scaffold proteins underlying tumorigenesis.” FEBS letters, vol.
583, no. 12, pp. 1817–24, Jun. 2009.
[26] H. Zhang, A. Photiou, G. Arnhild, J. Stebbing, and G. Giamas, "The
role of pseudokinases in cancer.” Cellular signalling, vol. 24, no. 6, pp.
1173–1184, Feb. 2012.
[27] A. S. Shaw and E. L. Filbert, "Scaffold proteins and immune-cell
signalling.” Nature reviews. Immunology, vol. 9, no. 1, pp. 47–56, Jan.
2009.
[28] A. Alexa, J. Varga, and A. Rem´enyi, "Scaffolds are ’active’ regulators of
signaling modules.” The FEBS journal, vol. 277, no. 21, pp. 4376–82,
Nov. 2010.
[29] M. Colledge and J. D. Scott, "AKAPs: from structure to function.”
Trends in cell biology, vol. 9, no. 6, pp. 216–21, Jun. 1999.
[30] M. M. McKay, D. a. Ritt, and D. K. Morrison, "Signaling dynamics of
the KSR1 scaffold complex.” Proceedings of the National Academy of
Sciences of the United States of America, vol. 106, no. 27, pp. 11 022–7,
Jul. 2009.
[31] F. Ram´ırez and M. Albrecht, "Finding scaffold proteins in interactomes.”
Trends in cell biology, vol. 20, no. 1, pp. 2–4, Jan. 2010.
[32] D. F. Brennan, A. C. Dar, N. T. Hertz, W. C. H. Chao, A. L. Burlingame,
K. M. Shokat, and D. Barford, "A Raf-induced allosteric transition of
KSR stimulates phosphorylation of MEK.” Nature, vol. 472, no. 7343,
pp. 366–9, Apr. 2011.
[33] W. G. Cance, E. Kurenova, T. Marlowe, and V. Golubovskaya,
"Disrupting the Scaffold to Improve Focal Adhesion Kinase-Targeted
Cancer Therapeutics,” Science Signaling, vol. 6, no. 268, pp. pe10–pe10,
Mar. 2013.
[34] T. S. Keshava Prasad, R. Goel, K. Kandasamy, S. Keerthikumar,
S. Kumar, S. Mathivanan, D. Telikicherla, R. Raju, B. Shafreen,
A. Venugopal, L. Balakrishnan, A. Marimuthu, S. Banerjee, D. S.
Somanathan, A. Sebastian, S. Rani, S. Ray, C. J. Harrys Kishore,
S. Kanth, M. Ahmed, M. K. Kashyap, R. Mohmood, Y. L.
Ramachandra, V. Krishna, B. A. Rahiman, S. Mohan, P. Ranganathan,
S. Ramabadran, R. Chaerkady, and A. Pandey, "Human Protein
Reference Database–2009 update.” Nucleic acids research, vol. 37, no.
Database issue, pp. D767–72, Jan. 2009.
[35] P. V. Hornbeck, I. Chabra, J. M. Kornhauser, E. Skrzypek, and B. Zhang,
"PhosphoSite: A bioinformatics resource dedicated to physiological
protein phosphorylation.” Proteomics, vol. 4, no. 6, pp. 1551–61, Jun.
2004.
[36] H. Dinkel, C. Chica, A. Via, C. M. Gould, L. J. Jensen, T. J.
Gibson, and F. Diella, "Phospho.ELM: a database of phosphorylation
sites–update 2011.” Nucleic acids research, vol. 39, no. November 2010,
pp. 261–267, Nov. 2010.
[37] J. M. Claverie and S. Audic, "The statistical significance of
nucleotide position-weight matrix matches.” Computer applications in
the biosciences : CABIOS, vol. 12, no. 5, pp. 431–9, Oct 1996.
[38] G. D. Stormo, "DNA binding sites: representation and discovery.”
Bioinformatics (Oxford, England), vol. 16, no. 1, pp. 16–23, Jan. 2000.
[39] R. Mosca, A. C´eol, and P. Aloy, "Interactome3D: adding structural
details to protein networks.” Nature methods, vol. 10, no. 1, pp. 47–53,
Dec. 2013.
[40] G. Badis, M. F. Berger, A. a. Philippakis, S. Talukder, A. R. Gehrke,
S. a. Jaeger, E. T. Chan, G. Metzler, A. Vedenko, X. Chen, H. Kuznetsov,
C.-F. Wang, D. Coburn, D. E. Newburger, Q. Morris, T. R. Hughes,
and M. L. Bulyk, "Diversity and complexity in DNA recognition by
transcription factors.” Science (New York, N.Y.), vol. 324, no. 5935, pp.
1720–3, Jun. 2009.
[41] D. Matenia and E.-M. Mandelkow, "The tau of MARK: a polarized view
of the cytoskeleton.” Trends in biochemical sciences, vol. 34, no. 7, pp.
332–42, Jul. 2009.
[42] A. Alonso, T. Zaidi, M. Novak, I. Grundke-Iqbal, and K. Iqbal,
"Hyperphosphorylation induces self-assembly of tau into tangles of
paired helical filaments/straight filaments.” Proceedings of the National
Academy of Sciences of the United States of America, vol. 98, no. 12,
pp. 6923–8, Jun. 2001.
[43] H. Matsuzaki, A. Ichino, T. Hayashi, T. Yamamoto, and U. Kikkawa,
"Regulation of intracellular localization and transcriptional activity of
FOXO4 by protein kinase B through phosphorylation at the motif sites
conserved among the FOXO family.” Journal of biochemistry, vol. 138,
no. 4, pp. 485–91, Oct. 2005.
[44] M. Punta, P. C. Coggill, R. Y. Eberhardt, J. Mistry, J. Tate, C. Boursnell,
N. Pang, K. Forslund, G. Ceric, J. Clements, A. Heger, L. Holm, E. L. L.
Sonnhammer, S. R. Eddy, A. Bateman, and R. D. Finn, "The Pfam
protein families database.” Nucleic acids research, vol. 40, no. Database
issue, pp. D290–301, Jan. 2012.
[45] M. Ashburner, C. A. Ball, J. A. Blake, D. Botstein, H. Butler, J. M.
Cherry, A. P. Davis, K. Dolinski, S. S. Dwight, J. T. Eppig, M. A.
Harris, D. P. Hill, L. Issel-Tarver, A. Kasarskis, S. Lewis, J. C. Matese,
J. E. Richardson, M. Ringwald, G. M. Rubin, and G. Sherlock, "Gene
ontology: tool for the unification of biology. The Gene Ontology
Consortium.” Nature genetics, vol. 25, no. 1, pp. 25–9, May 2000.
[46] A. Zeke, M. Luk´acs, W. a. Lim, and A. Rem´enyi, "Scaffolds: interaction
platforms for cellular signalling circuits.” Trends in cell biology, vol. 19,
no. 8, pp. 364–74, Aug. 2009.
[47] S. Karthikeyan, T. Leung, and J. A. A. Ladias, "Structural determinants
of the Na+/H+ exchanger regulatory factor interaction with the beta 2
adrenergic and platelet-derived growth factor receptors.” The Journal of
biological chemistry, vol. 277, no. 21, pp. 18 973–8, May 2002.
[48] K. Jiang, E. Pereira, M. Maxfield, B. Russell, D. M. Goudelock, and
Y. Sanchez, "Regulation of Chk1 includes chromatin association and
14-3-3 binding following phosphorylation on Ser-345.” The Journal of
biological chemistry, vol. 278, no. 27, pp. 25 207–17, Jul. 2003.
[49] G. A. Penman, L. Leung, and I. S. N¨athke, "The adenomatous polyposis
coli protein (APC) exists in two distinct soluble complexes with different
functions.” Journal of cell science, vol. 118, no. Pt 20, pp. 4741–50, Oct.
2005.
[50] C. Reichen, S. Hansen, and A. Plckthun, "Modular peptide binding:
From a comparison of natural binders to designed armadillo repeat
proteins,” Journal of Structural Biology, vol. In press, no. 0, p.
http://dx.doi.org/10.1016/j.jsb.2013.07.012, 2013.
[51] R. Roskoski, "ERK1/2 MAP kinases: structure, function, and
regulation.” Pharmacological research : the official journal of the Italian
Pharmacological Society, vol. 66, no. 2, pp. 105–43, Aug. 2012.
[52] A. C. Lloyd, "Distinct functions for ERKs?” Journal of Biology, vol. 5,
no. 5, p. 13, Jan. 2006.
@article{"International Journal of Biological, Life and Agricultural Sciences:67483", author = "Manuel A. Alonso-Tarajano and Roberto Mosca and Patrick Aloy", title = "Systematic Identification and Quantification of Substrate Specificity Determinants in Human Protein Kinases", abstract = "Protein kinases participate in a myriad of cellular
processes of major biomedical interest. The in vivo substrate
specificity of these enzymes is a process determined by several
factors, and despite several years of research on the topic, is still
far from being totally understood. In the present work, we have
quantified the contributions to the kinase substrate specificity of
i) the phosphorylation sites and their surrounding residues in the
sequence and of ii) the association of kinases to adaptor or scaffold
proteins. We have used position-specific scoring matrices (PSSMs),
to represent the stretches of sequences phosphorylated by 93 families
of kinases. We have found negative correlations between the number
of sequences from which a PSSM is generated and the statistical
significance and the performance of that PSSM. Using a subset
of 22 statistically significant PSSMs, we have identified specificity
determinant residues (SDRs) for 86% of the corresponding kinase
families. Our results suggest that different SDRs can function as
positive or negative elements of substrate recognition by the different
families of kinases. Additionally, we have found that human proteins
with known function as adaptors or scaffolds (kAS) tend to interact
with a significantly large fraction of the substrates of the kinases to
which they associate. Based on this characteristic we have identified
a set of 279 potential adaptors/scaffolds (pAS) for human kinases,
which is enriched in Pfam domains and functional terms tightly
related to the proposed function. Moreover, our results show that
for 74.6% of the kinase–pAS association found, the pAS colocalize
with the substrates of the kinases they are associated to. Finally, we
have found evidence suggesting that the association of kinases to
adaptors and scaffolds, may contribute significantly to diminish the
in vivo substrate crossed-specificity of protein kinases. In general, our
results indicate the relevance of several SDRs for both the positive
and negative selection of phosphorylation sites by kinase families and
also suggest that the association of kinases to pAS proteins may be
an important factor for the localization of the enzymes with their set
of substrates.
", keywords = "Kinase, phosphorylation, substrate specificity, adaptors, scaffolds, cellular colocalization.", volume = "8", number = "6", pages = "592-10", }
