Fritz, Hans

Magdolen, Viktor

Schmitt, Manfred

Sommerhoff, Christian P.

English

Open Access LMU ( Ludwig-Maximilians-Univ. München)

Biol. Chem., Vol. 391, pp. 295–297, April 2010 • Copyright  by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2010.0482010/290110Article in press - uncorrected proofGuest EditorialThe 3rd International Symposium on Kallikreinsand Kallikrein-Related PeptidasesThe 3rd International Symposium on Kallikreins and Kalli-krein-Related Peptidases (IKS 2009) took place from August30 to September 2, 2009, in Munich, Germany. Pioneeringwork of H. Kraut, E.-K. Frey, and E. Werle conducted herein Munich in the first half of the last century led to theidentification of tissue kallikrein as the proteolytic enzymeliberating the vasoactive peptide kallidin from its substratelow-molecular-weight kininogen. As we know today, tissuekallikrein (KLK1) is just one member of the human kalli-krein-related peptidase family (for reviews see, e.g., Lund-wall et al., 2006; Lundwall and Brattsand, 2008; Sot-iropoulou et al., 2009). This family encompasses 15 KLKgenes located on chromosome 19q13.4 and constitutes thelargest cluster of serine proteases in the human genome.KLKB1, the gene encoding plasma kallikrein, which is moreclosely related to blood coagulation factor XI than to KLK1,is located on a different chromosome, 4q35.In contrast to KLK1, the other members of the KLK fam-ily display weak or no kininogenase activity. KLK1 thus isthe only ‘true’ tissue kallikrein, whereas the kallikrein-relat-ed peptidases target other substrates and fulfill other func-tions. The highly homologous members KLK1, KLK2(glandular kallikrein), and KLK3 (prostate-specific antigen,PSA) form a subgroup within the KLK family (named ‘clas-sical’ KLKs) sharing the so-called kallikrein-loop, a unique11-residue insertion in the 99-loop of serine proteases thatlies just above the active-site cleft and strongly impactsenzyme/substrate interactions. Whereas KLK1, -2, and -3have been known for a long time, the other members of theKLK family were identified rather late in the 1990s. AllKLKs are produced as single-chain pre-pro-proteases con-taining a single chymotrypsin- or trypsin-like catalytic do-main. After secretion as inactive zymogens, the KLKs areextracellularly activated by removal of their short propep-tides. The majority of these kallikrein-related peptidasesprefer, like trypsin, basic P1 residues, whereas few mem-bers cleave similar to chymotrypsin or with a mixed P1specificity.The identification of the KLK gene cluster has boostedintensive research focusing on the analysis of the(patho)physiological functions of the KLK proteases. Morethan 150 participants from 20 different countries (14 Euro-pean countries, USA, Canada, Australia, Japan, Mexico, andBrazil) attended the symposium in Munich that was sup-ported in particular by the German Research Association(DFG), the International Union for Biochemistry and Molec-ular Biology, and the E.K. Frey-E. Werle Foundation.The research progress in the KLK field presented and dis-cussed at the symposium is particularly exemplified by thework of the recipients of the three awards presented by theE.K. Frey-E. Werle Foundation. The ‘Commemorative GoldMedal’ was given to Michael Blaber, mainly for his funda-mental findings on the involvement of KLK6 in neurologicaldisorders and the elucidation of activation relationships with-in the KLK family and with the thrombostasis system. In2002, Blaber and colleagues solved the crystal structure ofthe first mature, active human kallikrein-related peptidase,KLK6, which is abundantly expressed in the central nervoussystem. At the same time, the structure of pro-KLK6 wasreported displaying a completely closed specificity pocketand other striking structural differences. Comparison of bothstructures allowed a detailed analysis of rearrangementsoccurring upon proteolytic activation. Meanwhile, the struc-tures of several other human KLK proteases, i.e., KLK1, -3,-4, -5, and -7, have been published.In normal and malignant tissues, members of the kallikreinfamily and various other endopeptidases are coexpressed,raising the possibility that KLKs can participate in proteo-lytic cascades. To analyze the activation of the human pro-KLKs, Blaber and coworkers established a high-throughputsystem allowing characterization of KLK propeptide cleav-age. For this, all propeptides of the KLK protease familywere individually fused to a soluble, protease-resistant carrierprotein and these fusion proteins incubated with matureKLKs or other active proteases revealing a series of potentialactivating pairs (for a review see Blaber et al., 2010). Otherfindings emphasize that KLKs are integrated within proteo-lytic networks. Several trypsin-like KLKs have, e.g., beenshown to be potent activators of the zymogens of the serineprotease urokinase-type plasminogen activator (uPA) as wellas the metalloproteases meprin a and b. Interestingly, in acomplementary setting, meprin b cleaves pro-KLK7 twoamino acids upstream its activation cleavage site. Such pro-cessing, although leaving the zymogen inactive, can primepro-KLK7 towards further activation by endoproteases and,potentially, exoproteases as well (Ohler et al., 2010).Many members of the KLK family represent biomarkers,particularly in prostate, ovarian, colon, and breast cancer,either regarding prediction of the course of the disease (prog-nosis) or response to therapy. Andreas Scorilas received the‘E.K. Frey-E. Werle Promotion Prize’ for his innovativeinvestigations on the development of highly sensitive quan-titative assays for biomarkers, particularly KLKs, and theevaluation of their clinical relevance. In the present highlightBereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 07.11.13 15:06296 Guest EditorialArticle in press - uncorrected proofissue, effects on KLK5 gene expression in prostate cancercells upon treatment with chemotherapeutic agents aredescribed (Mavridis et al., 2010). Analysis of mRNA expres-sion of the KLK gene family is complex, as alternative splic-ing is frequent. Increased expression of an alternativelyspliced KLK3 variant was observed in prostate cancer(Whitbread et al., 2010). In addition to mRNA quantificationand determination of protein levels by ELISA, expression ofKLK proteases within normal and malignant tissues has beenextensively analyzed by immunohistochemical methods (see,e.g., Gabril et al., 2010, and Seiz et al., 2010). To investigatethe levels of kallikrein-related peptidase activity in asciticfluids of ovarian cancer patients, an irreversible inhibitor oftrypsin-like proteases, hooked to biotin via a chemical linker,was used to precipitate proteases with streptavidin-coatedmagnetic beads (Oikonomopoulou et al., 2010a). Interesting-ly, only low levels of active KLK enzymes relative to thetotal amounts determined by ELISA were present in theseascitic fluids. One possible explanation is that active KLKproteases rapidly form complexes with natural inhibitors alsopresent in ascitic fluids. Nevertheless, as over- or de novoexpression of KLKs is often associated with poor patientoutcome, these proteases certainly represent attractive targetsfor tumor therapy. Although still a matter of debate, evenKLK3 (prostate-specific antigen, PSA), which at present isclinically used as a diagnostic and monitoring marker, couldbe a candidate for cancer treatment by inhibiting its proteo-lytic activity (LeBeau et al., 2010). The use of engineeredsunflower trypsin inhibitors to target KLK4 or KLK14(Swedberg et al., 2010) or other scaffolds such as ecotin(Stoop et al., 2010) could allow a tight control of proteolyticactivity in cancer patients. Furthermore, cyclic peptides weredeveloped to inhibit the proteolytic activity of KLK2 (Hekimet al., 2010). A novel approach to regulate KLK overpro-duction is the use of microRNAs, small RNAs that do notcode for proteins but function by controlling the expressionof other genes (White et al., 2010).In addition to their contribution to the degradation ofextracellular matrix proteins and their supposable involve-ment in inflammatory pathways (Sotiropoulou and Pampa-lakis, 2010), it is now clear that certain KLKs serve assignaling molecules controlling cell functions through spe-cific membrane receptors, the protease-activated receptors(PARs). The signals, induced by proteolytic cleavage of thereceptors, modulate processes including platelet aggregation,vascular relaxation, cell proliferation, cytokine release, andinflammation. Katerina Oikonomopoulou, recipient of the‘E.K. Frey–E. Werle Young Investigator Award 2009’, dem-onstrated in cell model systems that KLK5, -6, and -14 canactivate PAR1, -2, and -4 to different extents (reviewed inOikonomopoulou et al., 2010b). Together with independentwork by other groups, these results suggest that some KLKproteases could be major modulators of PAR-mediated sig-naling in inflammatory diseases and/or cancer.Although the emphasis of the IKS 2009 symposium inMunich was on the analysis of the (patho)physiological func-tions of the ‘new’ kallikreins KLK4–KLK15, it offered aseries of presentations on the progress in research concerningthe ‘classical’ kallikreins KLK1–KLK3 as well. This isreflected by several articles in the present highlight issue,including a review on the role of KLK1 in various types ofdiseases and wound healing (Chao et al., 2010), the pres-entation of a protein network linking the kallikrein-kinin andrenin-angiotensin systems developed by employing three-dimensional protein-protein interaction databases (Stoka andTurk, 2010), and the analysis of transgenic mice expressingrat tonin, the homolog of KLK2, in the brain (Cardoso et al.,2010). In the case of KLK1 and KLK8, knockout mousemodels have also been utilized to elucidate their physiolog-ical functions. Interestingly, analyses of KLK8-/- mice indi-cate that this protease can also have functions in the brainas well as in the skin (see Yoshida, 2010).ReferencesBlaber, M., Yoon, H., Juliano, M.A., Scarisbrick, I.A., and Blaber,S.I. (2010). Functional intersection of the kallikrein-related pep-tidases (KLKs) and thrombostasis axis. Biol. Chem. 391,311–320.Cardoso, C.C., Alenina, N., Ferreira, A.J., Qadri, F., Lima, M.P.,Gross, V., Todiras, M., Pesquero, J.B., Pesquero, J.L., and Bader,M. (2010). Increased blood pressure and water intake in trans-genic mice expressing rat tonin in the brain. Biol. Chem. 391,435–441.Chao, J., Shen, B., Gao, L., Xia, C.-F., Bledsoe, G., and Chao, L.(2010). Tissue kallikrein in cardiovascular, cerebrovascular andrenal diseases and skin wound healing. Biol. Chem. 391,345–355.Gabril, M., White, N.M., Moussa, M., Chow, T.F., Metias, S.M.,Fatoohi, E., and Yousef, G.M. (2010). Immunohistochemicalanalysis of kallikrein-related peptidases in the normal kidney andrenal tumors: potential clinical implications. Biol. Chem. 391,403–409.Hekim, C., Riipi, T., Weisel, J., Na¨rva¨nen, A., Koistinen, R., Sten-man, U.-H., and Koistinen, H. (2010). Identification of IGFBP-3 fragments generated by KLK2 and prevention of fragmentationby KLK2-inhibiting peptides. Biol. Chem. 391, 475–479.LeBeau, A.M., Kostova, M., Craik, C.S., and Denmeade, S.R.(2010). Prostate-specific antigen: an overlooked candidate forthe targeted treatment and selective imaging of prostate cancer.Biol. Chem. 391, 333–343.Lundwall, A. and Brattsand, M. (2008). Kallikrein-related peptid-ases. Cell. Mol. Life Sci. 65, 2019–2038.Lundwall, A., Band, V., Blaber, M., Clements, J.A., Courty, Y., Dia-mandis, E.P., Fritz, H., Lilja, H., Malm, J., Maltais, L.J., et al.(2006). A comprehensive nomenclature for serine proteases withhomology to tissue kallikreins. Biol. Chem. 387, 637–641.Mavridis, K., Talieri, M., and Scorilas, A. (2010). KLK5 geneexpression is severely upregulated in androgen-independentprostate cancer cells after treatment with the chemotherapeuticagents docetaxel and mitoxantrone. Biol. Chem. 391, 467–474.Ohler, A., Debela, M., Wagner, S., Magdolen, V., and Becker-Pauly,C. (2010). Analyzing the protease web in skin: meprin metal-loproteases are activated specifically by KLK4, 5 and 8 viceversa leading to processing of proKLK7 thereby triggering itsactivation. Biol. Chem. 391, 455–460.Oikonomopoulou, K., Batruch, I., Smith, C.R., Soosaipillai, A., Dia-mandis, E.P., and Hollenberg, M.D. (2010a). Functional proteo-Bereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 07.11.13 15:06Guest Editorial 297Article in press - uncorrected proofmics of kallikrein-related peptidases in ovarian cancer ascitesfluid. Biol. Chem. 391, 381–390.Oikonomopoulou, K., Diamandis, E.P., and Hollenberg, M.D.(2010b). Kallikrein-related peptidases: proteolysis and signallingin cancer, the new frontier. Biol. Chem. 391, 299–310.Seiz, L., Kotzsch, M., Grebenchtchikov, N., Geurts-Moespot, A.,Fuessel, S., Goettig, P., Gkazepis, A., Wirth, M.P., Schmitt, M.,Loßnitzer, A., et al. (2010). Polyclonal antibodies against kalli-krein-related peptidase 4 (KLK4): immuno-histochemical assess-ment of KLK4 expression in healthy tissues and prostate cancer.Biol. Chem. 391, 391–401.Sotiropoulou, G. and Pampalakis, G. (2010). Kallikrein-related pep-tidases: bridges between immune functions and extracellularmatrix degradation. Biol. Chem. 391, 321–331.Sotiropoulou, G., Pampalakis, G., and Diamandis, E.P. (2009).Functional roles of human kallikrein-related peptidases. J. Biol.Chem. 284, 32989–32994.Stoka, V. and Turk, V. (2010). A structural network associated withthe kallikrein-kinin and renin-angiotensin systems. Biol. Chem.391, 443–454.Stoop, A.A., Joshi, R.V., Eggers, C.T., and Craik, C.S. (2010). Anal-ysis of an engineered plasma kallikrein inhibitor and its effecton contact activation. Biol. Chem. 391, 425–433.Swedberg, J.E., de Veer, S.J., and Harris, J.M. (2010). Natural andengineered kallikrein inhibitors: an emerging pharmacopeia.Biol. Chem. 391, 357–374.Whitbread, A.K., Veveris-Lowe, T.L., Dong, Y., Tan, O.L., Gardiner,R., Samaratunga, H.M., Nicol, D.L., and Clements, J.A. (2010).Expression of PSA-RP2, an alternatively spliced variant fromthe PSA gene, is increased in prostate cancer tissues but theprotein is not secreted from prostate cancer cells. Biol. Chem.391, 461–466.White, N.M., Bui, A., Mejia-Guerrero, S., Chao, J., Soosaipillai, A.,Youssef, Y., Mankaruos, M., Honey, R.J., Stewart, R., Pace, K.T.,et al. (2010). Dysregulation of kallikrein-related peptidases inrenal cell carcinoma: potential targets of miRNAs. Biol. Chem.391, 411–423.Yoshida, S. (2010). Klk8, a multifunctional protease in the brainand skin: analysis of knockout mice. Biol. Chem. 391, 375–380.Viktor Magdolen and Manfred SchmittClinical Research UnitDepartment of Obstetrics and GynecologyTechnical University MunichIsmaninger Str. 22D-81675 MunichGermanye-mail: viktor.magdolen@lrz.tum.de;manfred.schmitt@lrz.tum.deChristian P. Sommerhoff and Hans FritzDivision of Clinical Chemistry and Clinical BiochemistryMedical Faculty of theLudwig Maximilians University MunichNussbaumstr. 20D-80336 MunichGermanye-mail: sommerhoff@med.uni-muenchen.de;fritz@med.uni-muenchen.deBereitgestellt von | Universitaetsbibliothek der LMU MuenchenAngemeldet | 129.187.254.47Heruntergeladen am | 07.11.13 15:06

A comprehensive nomenclature for serine proteases with homology to tissue kallikreins.

A structural network associated with the kallikrein-kinin and renin-angiotensin systems.

Analysis of an engineered plasma kallikrein inhibitor and its effect on contact activation.

Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation.

Dysregulation of kallikrein-related peptidases in renal cell carcinoma: potential targets of miRNAs.

Expression of PSA-RP2, an alternatively spliced variant from the PSA gene, is increased in prostate cancer tissues but the protein is not secreted from prostate cancer cells.

Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axis.

Functional roles of human kallikrein-related peptidases.

Identification of IGFBP3 fragments generated by KLK2 and prevention of fragmentation by KLK2-inhibiting peptides.

Immunohistochemical analysis of kallikrein-related peptidases in the normal kidney and renal tumors: potential clinical implications.

Increased blood pressure and water intake in transgenic mice expressing rat tonin in the brain.

Kallikrein-related peptidases: bridges between immune functions and extracellular matrix degradation.

Kallikrein-related peptidases: proteolysis and signalling in cancer, the new frontier.

Kallikrein-related peptidases.

KLK5 gene expression is severely upregulated in androgen-independent prostate cancer cells after treatment with the chemotherapeutic agents docetaxel and mitoxantrone.

Klk8, a multifunctional protease in the brain and skin: analysis of knockout mice.

Natural and engineered kallikrein inhibitors: an emerging pharmacopeia.

Polyclonal antibodies against kallikrein-related peptidase 4 (KLK4): immuno-histochemicalassessment of KLK4 expression in healthy tissues and prostate cancer.

press - uncorrected proof mics of kallikrein-related peptidases in ovarian cancer ascites fluid.

Prostate-specific antigen: an overlooked candidate for the targeted treatment and selective imaging of prostate cancer.

Tissue kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing.

The 3(rd) International Symposium on Kallikreins and Kallikrein-Related Peptidases

Crossref

The 3rd International Symposium on Kallikreins and Kallikrein-Related Peptidases

Universität München: Elektronischen Publikationen

Biol. Chem., Vol. 391, pp. 295–297, April 2010 • Copyright  by Walter de Gruyter • Berlin • New York. DOI 10.1515/BC.2010.048
2010/290110
Article in press - uncorrected proof
Guest Editorial
The 3rd International Symposium on Kallikreins
and Kallikrein-Related Peptidases
The 3rd International Symposium on Kallikreins and Kalli-
krein-Related Peptidases (IKS 2009) took place from August
30 to September 2, 2009, in Munich, Germany. Pioneering
work of H. Kraut, E.-K. Frey, and E. Werle conducted here
in Munich in the first half of the last century led to the
identification of tissue kallikrein as the proteolytic enzyme
liberating the vasoactive peptide kallidin from its substrate
low-molecular-weight kininogen. As we know today, tissue
kallikrein (KLK1) is just one member of the human kalli-
krein-related peptidase family (for reviews see, e.g., Lund-
wall et al., 2006; Lundwall and Brattsand, 2008; Sot-
iropoulou et al., 2009). This family encompasses 15 KLK
genes located on chromosome 19q13.4 and constitutes the
largest cluster of serine proteases in the human genome.
KLKB1, the gene encoding plasma kallikrein, which is more
closely related to blood coagulation factor XI than to KLK1,
is located on a different chromosome, 4q35.
In contrast to KLK1, the other members of the KLK fam-
ily display weak or no kininogenase activity. KLK1 thus is
the only ‘true’ tissue kallikrein, whereas the kallikrein-relat-
ed peptidases target other substrates and fulfill other func-
tions. The highly homologous members KLK1, KLK2
(glandular kallikrein), and KLK3 (prostate-specific antigen,
PSA) form a subgroup within the KLK family (named ‘clas-
sical’ KLKs) sharing the so-called kallikrein-loop, a unique
11-residue insertion in the 99-loop of serine proteases that
lies just above the active-site cleft and strongly impacts
enzyme/substrate interactions. Whereas KLK1, -2, and -3
have been known for a long time, the other members of the
KLK family were identified rather late in the 1990s. All
KLKs are produced as single-chain pre-pro-proteases con-
taining a single chymotrypsin- or trypsin-like catalytic do-
main. After secretion as inactive zymogens, the KLKs are
extracellularly activated by removal of their short propep-
tides. The majority of these kallikrein-related peptidases
prefer, like trypsin, basic P1 residues, whereas few mem-
bers cleave similar to chymotrypsin or with a mixed P1
specificity.
The identification of the KLK gene cluster has boosted
intensive research focusing on the analysis of the
(patho)physiological functions of the KLK proteases. More
than 150 participants from 20 different countries (14 Euro-
pean countries, USA, Canada, Australia, Japan, Mexico, and
Brazil) attended the symposium in Munich that was sup-
ported in particular by the German Research Association
(DFG), the International Union for Biochemistry and Molec-
ular Biology, and the E.K. Frey-E. Werle Foundation.
The research progress in the KLK field presented and dis-
cussed at the symposium is particularly exemplified by the
work of the recipients of the three awards presented by the
E.K. Frey-E. Werle Foundation. The ‘Commemorative Gold
Medal’ was given to Michael Blaber, mainly for his funda-
mental findings on the involvement of KLK6 in neurological
disorders and the elucidation of activation relationships with-
in the KLK family and with the thrombostasis system. In
2002, Blaber and colleagues solved the crystal structure of
the first mature, active human kallikrein-related peptidase,
KLK6, which is abundantly expressed in the central nervous
system. At the same time, the structure of pro-KLK6 was
reported displaying a completely closed specificity pocket
and other striking structural differences. Comparison of both
structures allowed a detailed analysis of rearrangements
occurring upon proteolytic activation. Meanwhile, the struc-
tures of several other human KLK proteases, i.e., KLK1, -3,
-4, -5, and -7, have been published.
In normal and malignant tissues, members of the kallikrein
family and various other endopeptidases are coexpressed,
raising the possibility that KLKs can participate in proteo-
lytic cascades. To analyze the activation of the human pro-
KLKs, Blaber and coworkers established a high-throughput
system allowing characterization of KLK propeptide cleav-
age. For this, all propeptides of the KLK protease family
were individually fused to a soluble, protease-resistant carrier
protein and these fusion proteins incubated with mature
KLKs or other active proteases revealing a series of potential
activating pairs (for a review see Blaber et al., 2010). Other
findings emphasize that KLKs are integrated within proteo-
lytic networks. Several trypsin-like KLKs have, e.g., been
shown to be potent activators of the zymogens of the serine
protease urokinase-type plasminogen activator (uPA) as well
as the metalloproteases meprin a and b. Interestingly, in a
complementary setting, meprin b cleaves pro-KLK7 two
amino acids upstream its activation cleavage site. Such pro-
cessing, although leaving the zymogen inactive, can prime
pro-KLK7 towards further activation by endoproteases and,
potentially, exoproteases as well (Ohler et al., 2010).
Many members of the KLK family represent biomarkers,
particularly in prostate, ovarian, colon, and breast cancer,
either regarding prediction of the course of the disease (prog-
nosis) or response to therapy. Andreas Scorilas received the
‘E.K. Frey-E. Werle Promotion Prize’ for his innovative
investigations on the development of highly sensitive quan-
titative assays for biomarkers, particularly KLKs, and the
evaluation of their clinical relevance. In the present highlight
Bereitgestellt von | Universitaetsbibliothek der LMU Muenchen
Angemeldet | 129.187.254.47
Heruntergeladen am | 07.11.13 15:06
296 Guest Editorial
Article in press - uncorrected proof
issue, effects on KLK5 gene expression in prostate cancer
cells upon treatment with chemotherapeutic agents are
described (Mavridis et al., 2010). Analysis of mRNA expres-
sion of the KLK gene family is complex, as alternative splic-
ing is frequent. Increased expression of an alternatively
spliced KLK3 variant was observed in prostate cancer
(Whitbread et al., 2010). In addition to mRNA quantification
and determination of protein levels by ELISA, expression of
KLK proteases within normal and malignant tissues has been
extensively analyzed by immunohistochemical methods (see,
e.g., Gabril et al., 2010, and Seiz et al., 2010). To investigate
the levels of kallikrein-related peptidase activity in ascitic
fluids of ovarian cancer patients, an irreversible inhibitor of
trypsin-like proteases, hooked to biotin via a chemical linker,
was used to precipitate proteases with streptavidin-coated
magnetic beads (Oikonomopoulou et al., 2010a). Interesting-
ly, only low levels of active KLK enzymes relative to the
total amounts determined by ELISA were present in these
ascitic fluids. One possible explanation is that active KLK
proteases rapidly form complexes with natural inhibitors also
present in ascitic fluids. Nevertheless, as over- or de novo
expression of KLKs is often associated with poor patient
outcome, these proteases certainly represent attractive targets
for tumor therapy. Although still a matter of debate, even
KLK3 (prostate-specific antigen, PSA), which at present is
clinically used as a diagnostic and monitoring marker, could
be a candidate for cancer treatment by inhibiting its proteo-
lytic activity (LeBeau et al., 2010). The use of engineered
sunflower trypsin inhibitors to target KLK4 or KLK14
(Swedberg et al., 2010) or other scaffolds such as ecotin
(Stoop et al., 2010) could allow a tight control of proteolytic
activity in cancer patients. Furthermore, cyclic peptides were
developed to inhibit the proteolytic activity of KLK2 (Hekim
et al., 2010). A novel approach to regulate KLK overpro-
duction is the use of microRNAs, small RNAs that do not
code for proteins but function by controlling the expression
of other genes (White et al., 2010).
In addition to their contribution to the degradation of
extracellular matrix proteins and their supposable involve-
ment in inflammatory pathways (Sotiropoulou and Pampa-
lakis, 2010), it is now clear that certain KLKs serve as
signaling molecules controlling cell functions through spe-
cific membrane receptors, the protease-activated receptors
(PARs). The signals, induced by proteolytic cleavage of the
receptors, modulate processes including platelet aggregation,
vascular relaxation, cell proliferation, cytokine release, and
inflammation. Katerina Oikonomopoulou, recipient of the
‘E.K. Frey–E. Werle Young Investigator Award 2009’, dem-
onstrated in cell model systems that KLK5, -6, and -14 can
activate PAR1, -2, and -4 to different extents (reviewed in
Oikonomopoulou et al., 2010b). Together with independent
work by other groups, these results suggest that some KLK
proteases could be major modulators of PAR-mediated sig-
naling in inflammatory diseases and/or cancer.
Although the emphasis of the IKS 2009 symposium in
Munich was on the analysis of the (patho)physiological func-
tions of the ‘new’ kallikreins KLK4–KLK15, it offered a
series of presentations on the progress in research concerning
the ‘classical’ kallikreins KLK1–KLK3 as well. This is
reflected by several articles in the present highlight issue,
including a review on the role of KLK1 in various types of
diseases and wound healing (Chao et al., 2010), the pres-
entation of a protein network linking the kallikrein-kinin and
renin-angiotensin systems developed by employing three-
dimensional protein-protein interaction databases (Stoka and
Turk, 2010), and the analysis of transgenic mice expressing
rat tonin, the homolog of KLK2, in the brain (Cardoso et al.,
2010). In the case of KLK1 and KLK8, knockout mouse
models have also been utilized to elucidate their physiolog-
ical functions. Interestingly, analyses of KLK8-/- mice indi-
cate that this protease can also have functions in the brain
as well as in the skin (see Yoshida, 2010).
References
Blaber, M., Yoon, H., Juliano, M.A., Scarisbrick, I.A., and Blaber,
S.I. (2010). Functional intersection of the kallikrein-related pep-
tidases (KLKs) and thrombostasis axis. Biol. Chem. 391,
311–320.
Cardoso, C.C., Alenina, N., Ferreira, A.J., Qadri, F., Lima, M.P.,
Gross, V., Todiras, M., Pesquero, J.B., Pesquero, J.L., and Bader,
M. (2010). Increased blood pressure and water intake in trans-
genic mice expressing rat tonin in the brain. Biol. Chem. 391,
435–441.
Chao, J., Shen, B., Gao, L., Xia, C.-F., Bledsoe, G., and Chao, L.
(2010). Tissue kallikrein in cardiovascular, cerebrovascular and
renal diseases and skin wound healing. Biol. Chem. 391,
345–355.
Gabril, M., White, N.M., Moussa, M., Chow, T.F., Metias, S.M.,
Fatoohi, E., and Yousef, G.M. (2010). Immunohistochemical
analysis of kallikrein-related peptidases in the normal kidney and
renal tumors: potential clinical implications. Biol. Chem. 391,
403–409.
Hekim, C., Riipi, T., Weisel, J., Närvänen, A., Koistinen, R., Sten-
man, U.-H., and Koistinen, H. (2010). Identification of IGFBP-
3 fragments generated by KLK2 and prevention of fragmentation
by KLK2-inhibiting peptides. Biol. Chem. 391, 475–479.
LeBeau, A.M., Kostova, M., Craik, C.S., and Denmeade, S.R.
(2010). Prostate-specific antigen: an overlooked candidate for
the targeted treatment and selective imaging of prostate cancer.
Biol. Chem. 391, 333–343.
Lundwall, A. and Brattsand, M. (2008). Kallikrein-related peptid-
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Viktor Magdolen and Manfred Schmitt
Clinical Research Unit
Department of Obstetrics and Gynecology
Technical University Munich
Ismaninger Str. 22
D-81675 Munich
Germany
e-mail: viktor.magdolen@lrz.tum.de;
manfred.schmitt@lrz.tum.de
Christian P. Sommerhoff and Hans Fritz
Division of Clinical Chemistry and Clinical Biochemistry
Medical Faculty of the
Ludwig Maximilians University Munich
Nussbaumstr. 20
D-80336 Munich
Germany
e-mail: sommerhoff@med.uni-muenchen.de;
fritz@med.uni-muenchen.de
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The 3(rd) International Symposium on Kallikreins and Kallikrein-Related Peptidases

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