Hematopoietic cell-specific lyn substrate (HCLS1 or HS1): A versatile actin-binding protein in leukocytes

Abstract

Leukocytes are constantly produced in the bone marrow and released into the circulation. Many different leukocyte subpopulations exist that exert distinct functions. Leukocytes are recruited to sites of inflammation and combat the cause of inflammation via many different effector functions. Virtually all of these processes depend on dynamic actin remodeling allowing leukocytes to adhere, migrate, phagocytose, and release granules. However, actin dynamics are not possible without actin‐binding proteins (ABP) that orchestrate the balance between actin polymerization, branching, and depolymerization. The homologue of the ubiquitous ABP cortactin in hematopoietic cells is hematopoietic cell‐specific lyn substrate‐1, often called hematopoietic cell‐specific protein‐1 (HCLS1 or HS1). HS1 has been reported in different leukocytes to regulate Arp2/3‐dependent migration. However, more evidence is emerging that HS1 functions go far beyond just being a direct actin modulator. For example, HS1 is important for the activation of GTPases and integrins, and mediates signaling downstream of many receptors including BCR, TCR, and CXCR4. In this review, we summarize current knowledge on HS1 functions and discuss them in a pathophysiologic context.

3D-STED Super-Resolution Microscopy Reveals Distinct Nanoscale Organization of the Hematopoietic Cell-Specific Lyn Substrate-1 (HS1) in Normal and Leukemic B Cells

“…We isolated primary leukemic B cells from PB samples obtained from patients ( n = 11) ( Supplementary Table 2 ; Hallek et al, 2008 ) with CLL and from healthy donors ( n = 6) for determining the endogenous HS1 localization at the increased resolution of the 3D-STED imaging. To evaluate possible differences in HS1 activity linked to its localization and intracellular nanostructure in CLL, we stratified the patients based on the mutational status of the IGHV being HS1 downstream the B cell receptor ( Castro-Ochoa et al, 2019 ). We considered that, in CLL patients managed with active surveillance, the IGHV unmutated status is the biomarker with the strongest effect on time to first treatment prognostication ( Condoluci et al, 2020 ).…”

“…The multi-domain sequence of HS1 is responsible for the recruitment of the protein in different mechanisms such as the activation of GTPases and integrins and the downstream signaling of BCR and TCR, and is indispensable for signaling events leading to actin assembly during immunological synapse (IS) formation (reviewed in Gomez et al, 2006 ; Castro-Ochoa et al, 2019 ). The HS1 sequence contains also a nuclear localization signal ( van Rossum et al, 2005 ), for shuttling the transcription factor LEF-1 to the nucleus of myeloid cells ( Skokowa et al, 2012 ).…”

Saliva proteomic patterns in patients with molar incisor hypomineralization

“…In line with this concept, KEGG enrichment revealed HCLS1 and TUBA4A to be enriched for Pathogenic Escherichia coli infection (hsa05130; 2/53) and Tight junction (hsa04530; 2/167). For example, hematopoietic cell-specific protein-1 (HCLS1) regulates leukocyte actin remodeling and thereby their recruitment to sites of inflammation 77 . Further indicative of cytoskeletal effects, TUBA4A was enriched, however its role in oral health remains unclear 78 .…”

Chemical genetics strategy to profile kinase target engagement reveals role of FES in neutrophil phagocytosis via SYK activation

“…It can be phosphorylated on multiple tyrosine residues that all contribute to its actin remodeling function. 64 Of note, its Y378 and Y397 residues are phosphorylated by FES in mast cells, but both sites have also been identified as substrate sites for other kinases, including SYK. 19 Phosphorylation of HS1 by FES and/or SYK drives reorganization of the actin cytoskeleton required for internalization of the bacteriumreceptor complex ( Figure 6K, panel 3).…”