Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis
Abstract
:1. Introduction
2. The Regulated Localization of TKS Proteins Determines Their Signal Recruiting Function
3. TKS4 and TKS5 Affect Multiple Biological Processes from Growth Factor Receptor Signaling to Metastasis to Tissue Homeostasis
3.1. EGFR Signaling via TKS4 and TKS5
3.2. Molecular Organizers of Podosome and Invadopodium Assembly
3.3. Significance of TKS5 in Invasiveness
3.4. The Possible Role of TKS4 and TKS5 in the Compartmentalization of Oxidative Processes
3.5. Absence of TKS4 Induces Epithelial-Mesenchymal Transition (EMT) and Promotes Invasive Behavior
3.6. Cell Differentiation Modulated by TKS Molecules
3.7. Role of TKS4 in Tissue Homeostasis
4. TKS4- and TKS5-Related Pathological Conditions and Mouse Models
4.1. Pathological Conditions Related to TKS Protein Dysfunction
4.2. Knockout Mouse Models
5. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
Abbreviations
ADAM | a disintegrin and metalloproteinase |
BAT | brown adipose tissue |
BDCSS | Borrone dermato-cardio-skeletal syndrome |
ECM | extracellular matrix |
EGF | epidermal growth factor |
EMT | epithelial-mesenchymal transition |
FTHS | Frank-ter Haar syndrome |
GST | glutathione S-transferase |
H2O2 | hydrogen peroxide |
ITC | isothermal titration calorimetry |
KO | knockout |
MET | mesenchymal-epithelial transition |
miRNA | microRNA |
MMP | matrix metalloproteases |
mRNA | messenger RNA |
MSCs | mesenchymal stem/stromal cells |
nee mice | “nose-ear-eye” deformities mice |
NOX | NADPH oxidase |
O2- | superoxide anion |
˙OH | hydroxyl radical |
PI(4,5)P2 | phosphatidylinositol (4,5)-bisphosphate |
PI(3,4,5)P3 | phosphatidylinositol (3,4,5)-trisphosphate |
PPARγ | peroxisome proliferator-activated receptor gamma |
PRR | proline-rich region |
PTPases | phosphatases |
PX domain | Phox homology domain |
ROS | reactive oxygen species |
RTK | receptor tyrosine kinase |
SH3 | SRC homology 3 domain |
TKS | tyrosine kinase substrate |
UCP1 | uncoupling protein 1 |
WAT | white adipose tissue |
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(a) | |||
TKS4 | |||
Partner | Method | TKS4-Interacting Site | Function |
ADAM15 [34] | GST pull-down assay | 4th SH3 domain | Ectodomain shedding, cell adhesion, and signaling [35] |
Cortactin [9] | Co-immunoprecipitation, GST pull-down assay, immunofluorescence co-localization | Unknown | Regulation of actin cytoskeleton [36] |
CR16 [37] | GST pull-down assay | Weak interaction with the 2nd, 3rd, and 4th SH3 domains | Reorganization of actin cytoskeleton [38] |
DNM2 [37] | GST pull-down assay | 3rd SH3 domain | Endo-/exocytosis [37] |
FasL (CD178) [39] | Phage display screening | 3rd and 4th SH3 domains | Apoptosis induction [40] |
GRB2 [28] | Affinity purification–selected reaction monitoring mass spectrometry | Unknown | Adaptor protein involved in the regulation of RTK signaling, cycle progression, actin-based cell motility, podosome formation [41] |
NOXA1 [42,43] | Co-immunoprecipitation, GST pull-down assay | Unknown | ROS generation through NOX1 activation [44] |
N-WASP [37] | GST pull-down assay | 2nd SH3 domain | A scaffold protein regulating actin cytoskeleton reorganization, and actin polymerization during cell motility and invasion [45] |
OPHN1 [37] | GST pull-down assay | 3rd SH3 domain | Endo-/exocytosis [37] |
RUK/CIN85 [46] | GST pull-down assay | Unknown | Adaptor protein that recruits endocytotic regulatory proteins, and regulates RTK internalization, trafficking, and degradation [47] |
SRC [9,32] | Co-immunoprecipitation; GST pull-down and fluorescence-polaziation assays, Duolink proximity ligation assay | PRR (aa: 466–474); P-Tyr motif (aa: 508–511) | Regulation of cell growth, differentiation, proliferation, survival, adhesion, migration, and motility [9,32] |
SYNJ1 [37] | GST pull-down assay | 3rd SH3 domain and weak interaction with the 4th SH3 domain | Endo-/exocytosis [37] |
(b) | |||
TKS5 | |||
Partner | Method | TKS5-Interacting Site | Function |
ADAM12 [6] | Co-immunoprecipitation, immunofluorescence co-localization | 5th SH3 domain | Cell adhesion and fusion, extracellular matrix restructuring, reorganization of actin cytoskeleton, regulation of ectodomain shedding [48] |
ADAM15 [6] | Co-immunoprecipitation | 5th SH3 domain | Cell adhesion, degradation of ECM components, ectodomain shedding of membrane-bound growth factors [35] |
ADAM19 [6] | Phage display screen, co-immunoprecipitation | 5th SH3 domain | Extracellular matrix breakdown and reconstruction, ectodomain shedding, role in embryogenesis, cardiovascular system development, obesity, and insulin resistance [49] |
β-dystroglycan [50] | Phage display screen, GST pull-down assay, co-immunoprecipitation, immunofluorescence co-localization | 3rd SH3 domain | Links the extracellular matrix to the intracellular actin cytoskeleton [50] |
CircSKA3 [51] | Co-immunoprecipitation, pull-down assay | Not specified | Circular RNA, an inducer of invadopodium formation [51] |
Drebrin [52] | Co-immunoprecipitation | Unknown | An actin-binding protein involved in the regulation of actin filament organization, role in cell migration, cell process formation, intercellular communication, metastasis, and brain development [53] |
Dynamin [29,33] | Peptide spot membrane assay, GST pull-down assay, ITC, immunofluorescence co-localization, GST pull-down assay, mass spectrometry/Western blotting | 1st and 2nd SH3 domains; 1st and 5th SH3 domains | Regulation of actin cytoskeleton, podosome/invadopodium formation, role in endocytosis [54] |
F-actin [29] | GST pull-down assay, and mass spectrometry | 5th SH3 domain | Component of cytoskeleton [55] |
FasL (CD178) [39] | Phage display screening | 5th SH3 domain | Apoptosis induction [40] |
FGD1 [56] | Co-immunoprecipitation and mass spectrometry, GST pull-down assay, immunofluorescence co-localization | 4th and 5th SH3 domains | A guanine nucleotide exchange factor for the Rho-GTPase CDC42, assembly of podosomes and invadopodia, control of secretory membrane-trafficking, and cell cycle [56,57] |
Girdin [58] | Co-immunoprecipitation, immunofluorescence co-localization | Unknown | actin-binding protein regulating actin remodeling and cell polarity, collective migration of neuroblasts, epithelial and cancer cells [59] |
GRB2 [28,29] | Co-immunoprecipitation | Polyproline sequences | An adaptor protein involved in cell cycle progression and actin-based cell motility, podosome formation [41] |
IRTKS [60] | GST pull-down assay | First binding site located in the segment comprising the 1st and 2nd SH3 domains, second binding site located in the segment comprising the 3rd and 4th SH3 domains | Regulation of plasma membrane dynamics, actin cytoskeleton remodeling, cell migration and polarization, insulin signaling [61] |
MT4-MMP [62] | Co-immunoprecipitation | Unknown | Induction of invadopodia and amoeboid movement, degradation of ECM components, role in hypoxia-mediated metastasis [62] |
NCK [52] | Co-immunoprecipitation, fluorescence co-localization | Linker region between the 3rd and 4th SH3 domains containing pY557 | Adaptor protein involved in cytoskeletal remodeling, invadopodium formation, cell proliferation [63] |
Nogo-B [29] | GST pull-down assay and mass spectrometry | 5th SH3 domain | Roles in vascular remodeling, cell migration and proliferation, and EMT [64] |
NOXA1 [42,43] | Co-immunoprecipitation, GST pull-down assay | One or more of the five SH3 domains | ROS generation through NOX1 activation [44] |
N-WASP [29] | GST pull-down assay and mass spectrometry/Western blotting, co-immunoprecipitation | All five SH3 domains | A scaffold protein regulating actin cytoskeleton reorganization, and actin polymerization during cell motility and invasion [45] |
p22phox [65] | Co-immunoprecipitation | 1st and 2nd SH3 domains | Subunit of NADPH oxidases involved in ROS generation through NOX activity [66] |
Rab40b [67] | GST pull-down assay, co-immunoprecipitation, | PX-domain: sites 14-KRR-19 and Y24 in 23-YVYI-28 | A GTPase required for the sorting and secretion of MMP2 and MMP9, promotion of migration, invasion, and metastasis of cancer cells [67,68] |
RET [69] | Co-immunoprecipitation, immunofluorescence co-localization | Unknown | A receptor tyrosine kinase mediating stress fiber formation, cell polarization, directional migration and invasion, enhancement of proteolytic activity [69] |
SOS1 [33] | Immunofluorescence co-localization, peptide spot membrane assay, GST pull-down assay, isothermal titration calorimetry | 1st and 2nd SH3 domains * | A guanine nucleotide exchange factor promoting Ras and Rac activation downstream of a variety of receptors such as RTKs [70] |
Tubulin [29] | GST pull-down assay and mass spectrometry | 3rd SH3 domain | Component of microtubules, affects cell division, differentiation, intracellular transport, motility [71] |
WIP [29] | GST pull-down assay and mass spectrometry | 3rd and 5th SH3 domains | Regulation of actin cytoskeleton assembly and remodeling [72] |
XB130 [73] | Yeast two-hybrid screening, co-immunoprecipitation, GST pull-down assay, immunofluorescence co-localization | 5th SH3 domain | A scaffold protein influencing cell growth, survival, and migration [73] |
Zyxin [29] | GST pull-down assay and mass spectrometry | 3rd and 5th SH3 domains | A focal adhesion protein involved in actin cytoskeleton assembly [74] |
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Kudlik, G.; Takács, T.; Radnai, L.; Kurilla, A.; Szeder, B.; Koprivanacz, K.; Merő, B.L.; Buday, L.; Vas, V. Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis. Int. J. Mol. Sci. 2020, 21, 8117. https://doi.org/10.3390/ijms21218117
Kudlik G, Takács T, Radnai L, Kurilla A, Szeder B, Koprivanacz K, Merő BL, Buday L, Vas V. Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis. International Journal of Molecular Sciences. 2020; 21(21):8117. https://doi.org/10.3390/ijms21218117
Chicago/Turabian StyleKudlik, Gyöngyi, Tamás Takács, László Radnai, Anita Kurilla, Bálint Szeder, Kitti Koprivanacz, Balázs L. Merő, László Buday, and Virag Vas. 2020. "Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis" International Journal of Molecular Sciences 21, no. 21: 8117. https://doi.org/10.3390/ijms21218117