Proteomic Analysis of the Human Cyclin-dependent Kinase Family Reveals a Novel CDK5 Complex Involved in Cell Growth and Migration

Abstract

Cyclin-dependent kinases (CDKs) are the catalytic subunits of a family of mammalian heterodimeric serine/threonine kinases that play critical roles in the control of cell-cycle progression, transcription, and neuronal functions. However, the functions, substrates, and regulation of many CDKs are poorly understood. To systematically investigate these features of CDKs, we conducted a proteomic analysis of the CDK family and identified their associated protein complexes in two different cell lines using a modified SAINT (Significance Analysis of INTeractome) method. The mass spectrometry data were deposited to ProteomeXchange with identifier PXD000593 and DOI 10.6019/PXD000593. We identified 753 high-confidence candidate interaction proteins (HCIPs) in HEK293T cells and 352 HCIPs in MCF10A cells. We subsequently focused on a neuron-specific CDK, CDK5, and uncovered two novel CDK5-binding partners, KIAA0528 and fibroblast growth factor (acidic) intracellular binding protein (FIBP), in non-neuronal cells. We showed that these three proteins form a stable complex, with KIAA0528 and FIBP being required for the assembly and stability of the complex. Furthermore, CDK5-, KIAA0528-, or FIBP-depleted breast cancer cells displayed impaired proliferation and decreased migration, suggesting that this complex is required for cell growth and migration in non-neural cells. Our study uncovers new aspects of CDK functions, which provide direction for further investigation of these critical protein kinases. Molecular & Cellular

Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism

“…TMEM94 is known for the possible interaction with cyclin dependent kinase 5 (CDK5; MIM 123831) and acidic fibroblast growth factor intracellular-binding protein (FIBP; MIM 608296) in human embryonic kidney cells. [51][52][53] Our expression profiling studies did not reveal . Phenotypic and Histopathological Evaluation of Tmem94 Knockout Mice (A) Tmem94 À/À mice were embryonic lethal, hemorrhagic, and showed craniofacial abnormalities.…”

FOXR2 Interacts with MYC to Promote Its Transcriptional Activities and Tumorigenesis

“…To generate HCIP lists, we applied a modified SAINT algorithm, which uses a collection of TAP-MS results that follow the same protocol as the control group (Li et al, 2015b; Wang et al, 2014; Xu et al, 2014). We kept the same SAINT Score > 0.80 interactions as on the HCIP list.…”

Insights into the clinical value of cyclin-dependent kinase 5 in glioma: a retrospective study

“…Liu et al identified that CDK5-mediated phosphorylation of PIKE-A could activate AKT and enhance cell growth, as well as induce glioblastomas cell migration and invasion [ 15 ]. Previous studies also confirmed that CDK5 might be a critical player in cancer cell proliferation [ 12 , 22 ]. CDK5 also showed to promote prostate cancer cell growth through androgen receptor [ 33 ].…”

“…CDK5, one of the major kinases activated by its regulators p35 or p39, directly phosphorylates various residues and simultaneously regulates various substrates [ 7 ]. Evidence indicates that CDK5 may have extra neuronal functions that comprise transcript-selective translation control, glucose-inducible insulin secretion, vascular angiogenesis, cell adhesion, migration, and wound healing [ 22 , 23 ]. Previous studies demonstrated that CDK5 overexpression was implicated in the tumorigenesis and aggressiveness in several malignancies, for instance lung, pancreatic, neuroendocrine thyroid, and breast cancer [ 13 , 12 , 11 , 10 ].…”