The PEAK family of pseudokinases, their role in cell signalling and cancer

Abstract

The study of pseudokinases has uncovered that catalysis-independent functions play a critical role in cell signalling regulation. However, how pseudokinases dynamically assemble and regulate oncogenic signalling pathways remains, in most cases, unclear due to a limited knowledge of the structural determinants that are critical for their functions. Here, we review the recent progress made to unravel the role of the PEAK family of pseudokinases, which comprises SgK269, SgK223 and the recently identified PEAK3, in assembling specific oncogenic signalling pathways that contribute to the progression of several aggressive cancers. We focus on recent structural advances revealing that SgK269 and SgK223 can homo-and heteroassociate via a unique dimerisation domain, comprising conserved regulatory helices directly surrounding the pseudokinase domain, which is also conserved in PEAK3. We also highlight a potential oligomerisation mechanism driven by the pseudokinase domain. While it is likely that homo-or heterodimerisation and oligomerisation mechanisms contribute to the assembly of complex signalling hubs and provide a means to spatially and temporally modulate and diversify signalling outputs, the exact role that these oncogenic scaffolds play in regulating cell migration, invasion and morphology remains unclear. Here, we attempt to link their structural characteristics to their cellular functions by providing a thorough analysis of the signalling transduction pathways they are known to modulate.

PEAK3 pseudokinase represents a pro-migratory and -invasive signalling scaffold

“…The pseudokinases PEAK1 and 2 have emerged as key regulators of cell migration and signalling in both normal and cancer cells (Patel et al , 2020). Based on a shorter N-terminal extension and ability to block CrkII-enhanced membrane ruffling and cell morphology change, it was recently proposed the new family member PEAK3 might represent a negative regulator that antagonizes PEAK1/2 function (Lopez et al , 2019).…”

“…Three pseudokinases, PEAK1 (also known as SgK269), PEAK2 (SgK223/Pragmin) and the recently-identified PEAK3 (Chromosome 19 Open Reading Frame 35, C19orf35) form the PEAK family. These three proteins share highly conserved domain structures including a C-terminal pseudokinase (PsK) domain with adjacent N- and C-terminal α-helical regions (Patel et al , 2020). In addition, they all contain specific N-terminal extensions, which are long in PEAK1 (∼ 1,200 residues) and PEAK2 (∼900 residues), but much shorter in PEAK3 (∼ 100 residues) (Patel et al , 2020).…”

A SNAI2-PEAK1 stromal axis drives progression and lapatinib resistance in HER2-positive breast cancer by supporting a cytokine expression profile that converges on PI3K/Akt signaling

“…Pseudopodium-Enriched Atypical Kinase One (PEAK1 or SGK269) is a cytoskeletonassociated pseudokinase [12] and member of the new NFK3 kinase family that has been demonstrated to play key roles in cancer initiation and progression across multiple cancer types including breast [13][14][15], pancreatic [12,16], lung [17] and colon [12,18,19]. Importantly, two other NFK3 kinase family members (SGK223 or Pragmin and PEAK3) have been recently demonstrated to also regulate cancer progression [20,21]. We previously characterized breast cancer cell autonomous functions of PEAK1 and upstream eIF5A1/2-dependent translation in mediating epithelial-mesenchymal transition (EMT), metastasis and transforming growth factor beta (TGFβ)/fibronectin signaling [13][14][15]22].…”

The FEBS Journal in 2021: a sharp reminder that science really matters

“…We also published a Special Issue on 'Pseudoenzymes' (Fig. 2), edited by Colin Adrain (Queen's University, Belfast, N. Ireland) covering a diversity of topics highlighting the role of pseudoproteases, pseudokinases and pseudophosphatases, among other pseudoenzymes, in diverse biological processes ranging from cancer, inflammation, immunity and cell death [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. We are always very interested in hearing your proposals for Special Issues on cutting-edge topics of widespread interest; just email our editorial office with your proposal.…”