Cell News 2/2014
20
the cell cycle (Takaki et al., 2008). In addition to roles in centro-
some development, Plks 2 and 3 are also part of the DNA damage
response. Plk5, which lacks a kinase domain, is the most restricted
family member in terms of tissue specificity and function. It regu-
lates the formation of neurite processes (de Cárcer, 2011). Plk4 ser-
ves a specialized function in initiating centriole duplication (Bet-
tencourt-Dias et al., 2005 ; Habedanck et al., 2005), trophoblast
stem cell differentiation in cardiac morphogenesis (Martindill et
al., 2007) and cytokinesis (Rosario et al., 2010). Plk4 differs from
the other “canonical” members of the Plk family in several impor-
tant aspects (Leung et al., 2002). Most obviously, there are three
polo box (PB) domains in Plk4, compared with two in Plks1-3 ; mo-
reover, the Plks kinase domain shows high sequence similarity. The
C-terminal region of Plk4 is longer and features three PB domains
(PB1, PB2 and PB3). This distinct domain structure is reflected in
a major difference in tertiary structure and kinase activity. The
PB1 and PB2 domains of Plk1 associate to the kinase domain via
an intramolecular interaction, forming a functional auto-inhibited
unit (Fig. 2D). The binding of the phosphopeptide ligand to PB1
and PB2 leads to unfolding and exposure of the Plk1 kinase do-
main. The association of the ligand to PB1 and PB2 releases the
auto-inhibition and modulates the activity of the kinase domain
(Elia et al., 2003 ; Xu et al., 2013). By contrast, in Plk4 the PB3
domain and upstream cryptic polo box (PB1 and PB2) participate
in the intermolecular homodimerization. The binding of the Plk4
polo box domains is required for autophosphorylation in trans, and
hence kinase activation (Slevin et al., 2012 ; Park et al., 2014).
With respect to their biological role, early work showed increased
Plk4 expression in lymphoma and colorectal cancer (Fode et al.,
1994; Macmillan et al., 2001). In breast cancer, a synthetic lethal
interaction has recently been discovered between Plk4 and PTEN,
the Phosphatase and Tensin homolog (Brough et al., 2011). PTEN
is one of the most frequently inactivated tumor suppressor genes.
These pieces of evidence suggest that Plk4 expression may faci-
litate tumour progression. As for Plk1, recently a small molecu-
le inhibitor has been developed for Plk4, with selective targeting
aggressive cancer cells in mice from patient-derived tumor tissue
(Mason et al., 2014).
Conclusions
Examination of current studies based on X-ray crystallographic
studies revealed the relationship between structure and function
of the A-loop of protein kinases. This makes it a critical element
for protein kinase regulation. The activation segment is considered
as the primary determinant for substrate recognition. The descri-
bed substrate-recognition mechanisms in this report highlight the
involvement of short peptide motifs, which are unfolded or un-
structured in isolation and bind critical sites within a structured
protein domain. Furthermore, to enhance specificity, these recog-
nition mechanisms are often expanded by secondary interactions.
They constitute the secondary determinants for substrate recog-
nition. Their regulation through the interaction of intra-molecular
components within the respective protein kinases makes an addi-
tional control point for substrate recognition specificity.
Acknowledgments
The author thanks Harald Herrmann for critical review on the
manuscript. Y.Z.H. is research visitor in Harald Herrmann labo-
ratory at the DKFZ, Heidelberg and a recipient of the German
Academic Exchange Service (DAAD) grant.
Yosr Z. Haffani
High Institute of Biotechnology of Sidi Thabet Technopole of
Sidi-Thabet. University of Manouba, TUNISIA
Education and Research Experience
Since 2013: Professor Associate, High Institute of Biotechnology
at Sidi Thabet. Technopole. University of Manouba. Tunisia.
2006 - 2013: Post-Doctoral fellow at the Samuel Lunenfeld
Research Institute. Mount Sinai Hospital. Toronto. Canada.
Principal Investigator Dr Jim W Dennis
2003 - 2006: Post-Doctoral fellow at Samuel Lunenfeld Research
Institute. Mount Sinai Hospital. Toronto. Canada. Principal
Investigator Dr Frank Sicheri
2000 – 2003: Post-Doctoral fellow at University of Toronto,
Toronto. Canada. Principal Investigator Dr Daphne R. Goring
1994 – 2000: PhD in Molecular Biology. Université Laval.
Quebec. Canada. Principal Investigator Dr François Belzile
1991-1993: Master of Science degree in Fundamental and
Applied Genetics. Faculty of Science of Tunis. University El Manar,
Tunisia.
1987-1991: Bachelor with Honor in Natural Sciences. Faculty of
Science of Tunis, University El Manar. Tunisia.
Awards and Fellowships:
2014: DAAD Fellowship. Germany.
2009: 2nd prize of McMurrich Award poster competition.
University of Toronto. Toronto. Canada.
2008: 3rd prize of McMurrich Award poster competition.
University of Toronto. Toronto. Canada.
2005-2006: Samuel Lunenfield Research Institute Fellowship for
Post-Doctoral studies. Canada.
2001: Award of appreciation, Aventis Biotech Challenge. Toronto,
Canada.
1999-2000: FCAR Fellowship for doctoral studies. Quebec,
Canada.
1998: BioContact Quebec / ACFAS competition for best oral
presentation.
1994 - 1998: C.I.D.A. Fellowship from the Canadian Government
for doctoral studies.
References
Bettencourt-Dias, M., Rodrigues-Martins, A. et al. 2005. SAK/PLK4 is required for centriole dupli-
cation and flagella development. Cur. Biol. 15(24): 2199-2207.
Brinkworth, R. I., Breinl, R. A., Kobe, B. 2003 Structural basis and prediction of substrate specifi-
city in protein serine/ threonine kinases. Proc. Natl. Acad. Sci. USA 100: 74–79.
Brough, R., Frankum, J.R., Sims, D., et al. 2011. Functional viability profiles of breast cancer.
Cancer Discov. 1, 260–273.
Dar, A. C., Lopez, M. S., Shokat, K. M. 2008. Small molecule recognition of c-Src via the Imatinib-
binding conformation. Chem. Biol. 15: 1015-1022.
De Bondt, H. L., Rosenblatt, J., Jancarik, J., Jones, H.D., et al. 1993. Crystal structure of cyclin-
