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PurposeThe paper aims to explore how small- and medium-sized enterprises (SMEs) in the health-care sector overcome the liability of being an outsider, instead of gaining a position as an insider in new networks in markets abroad and subsequently internationalizing. The following research questions are posed: How do firms in complex health-care markets build network relationships? How is business market knowledge developed and legitimacy acquired to overcome the liability of outsidership?Design/methodology/approachThe paper uses a multiple-case methodology in a nested case study of health-care SMEs, which allows for in-depth study of the importance of network relationships, business market knowledge development and legitimacy building to enter a target market; the study maps the activities and different actor roles as the entry process unfolds. The study draws on empirical evidence from 13 companies as well as industry and interest organizations.FindingsThe results provide support for process-based explanations of how, but also of why the internationalization of health-care SMEs takes place in distinctive sequential phases, where it is necessary to complete one phase before it is possible to embark on the next. The study answers the calls for more empirical studies capturing how firms actively enter networks to overcome the liability of outsidership, become insiders and subsequently internationalize.Originality/valueThe principal contribution of the authors’ study is to add to the body of research on internationalization and advance the understanding of how to build an insidership position in relevant networks by overcoming the liability of outsidership. By choosing to study firms in the health-care sector, the authors also contribute to the limited research on firms entering markets characterized by a high level of complexity.

The aim of the study is to better understand start-ups' entrepreneurial business formation processes from a contextual perspective. We examine a digitalization process in the healthcare sector in Sweden, and investigate the start-up processes taking place in order to reach a better understanding of what it takes for new actors to obtain an insider position in this particular type of highly regulated networks. The study offers important insights into the dynamics of constituent elements in the process, including the sequences of events through which startup processes evolve, and insights into new ventures' initial entry into a business network. It is concluded that the studied processes were interactive, forcing the start-ups to be both innovative and able to conform. It was also found that legitimacy constitute an important resource in this type of politically sensitive context. Title in dissertation list of papers: Becoming a public sector insider: A case study of Start-ups´ Entrepreneurial Business Formation Processes in Swedish Digital Healthcare.

The adaptor protein Shb has previously been shown to regulate apoptosis in response to cytokines and inhibitors of angiogenesis although the mechanisms governing these effects have remained obscure. We currently demonstrate interactions between Shb and c-Abl and that Shb regulates c-Abl kinase activity. The data suggest that c-Abl binds to tyrosine phosphorylated Shb via a concerted effort involving both the c-Abl SH3 and SH2 domains. The biological significance of the Shb/c-Abl interaction was presently tested in overexpression experiments and was found to promote hydrogen peroxide-induced cell death. We also show by Shb knockdown experiments that Shb regulates c-Abl activity and modulates cell death in response to the genotoxic agent cisplatin and the endoplasmic reticulum stress-inducer tunicamycin. The findings are in agreement with the notion of Shb playing a pivotal role in modulating c-Abl pro-apoptotic signaling in response to various stress stimuli.

This study addresses the interactions between the adaptor protein Shb and components involved in T cell signalling, including SLP-76, Gads, Vav and ZAP70. We show that both SLP-76 and ZAP70 co-immunoprecipitate with Shb in Jurkat T cells and that Shb and Vav co-immunoprecipitate when cotransfected in COS cells. We also demonstrate, utilizing fusion protein constructs, that SLP-76, Gads and Vav associate independently of each other to different domains or regions, of Shb. Overexpression of an SH2 domain-defective Shb causes diminished phosphorylation of SLP-76 and Vav and consequently decreased activation of c-Jun kinase upon T cell receptor (TCR) stimulation. Shb was also found to localize to glycolipid-enriched membrane microdomains (GEMs), also called lipid rafts, after TCR stimulation. Our results indicate that upon TCR stimulation, Shb is targeted to these lipid rafts where Shb aids in recruiting the SLP-76–Gads–Vav complex to the T cell receptor ζ-chain and ZAP70.

Stimulation of the T cell antigen receptor (TCR) induces tyrosine phosphorylation of numerous intracellular proteins. We have recently investigated the role of the adaptor protein Shb in the early events of T cell signaling and observed that Shb associates with Grb2, linker for activation of T cells (LAT) and the TCR zeta-chain in Jurkat cells. We now report that Shb also associates with phospholipase C-gamma1 (PLC-gamma1) in these cells. Overexpression of Src homology 2 domain defective Shb caused diminished phosphorylation of LAT and consequently the activation of mitogen-activated protein kinases was decreased upon TCR stimulation. In addition, the Shb mutant also blocked phosphorylation of PLC-gamma1 and the increase in cytoplasmic Ca(2+) following TCR stimulation. Nuclear factor for activation of T cells is a major target for Ras and calcium signaling pathways in T cells following TCR stimulation, and the overexpression of the mutant Shb prevented TCR-dependent activation of the nuclear factor for activation of T cells. Consequently, endogenous interleukin-2 production was decreased under these conditions. The results indicate a role for Shb as a link between the TCR and downstream signaling events involving LAT and PLC-gamma1 and resulting in the activation of transcription of the interleukin-2 gene.

Definitive mesoderm arises from a bipotent mesendodermal population, and to study processes controlling its development at this stage, embryonic stem (ES) cells can be employed. SHB (Src homology 2 protein in β-cells) is an adapter protein previously found to be involved in ES cell differentiation to mesoderm. To further study the role of SHB in this context, we have established ES cell lines deficient for one (SHB+/-) or both SHB alleles (SHB-/-). Differentiating embryoid bodies (EBs) derived from these ES cell lines were used for gene expression analysis. Alternatively, EBs were stained for the blood vessel marker CD31. For hematopoietic differentiation, EBs were differentiated in methylcellulose. SHB-/- EBs exhibited delayed down-regulation of the early mesodermal marker Brachyury. Later mesodermal markers relatively specific for the hematopoietic, vascular, and cardiac lineages were expressed at lower levels on day 6 or 8 of differentiation in EBs lacking SHB. The expression of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 was also reduced in SHB-/- EBs. SHB-/- EBs demonstrated impaired blood vessel formation after vascular endothelial growth factor stimulation. In addition, the SHB-/- ES cells formed fewer blood cell colonies than SHB+/+ ES cells. It is concluded that SHB is required for appropriate hematopoietic and vascular differentiation and that delayed down-regulation of Brachyury expression may play a role in this context.

Recent experiments have unravelled novel signal transduction pathways that involve the SRC homology 2 (SH2) domain adapter protein SHB. SHB is ubiquitously expressed and contains proline rich motifs, a phosphotyrosine binding (PTB) domain, tyrosine phosphorylation sites and an SH2 domain and serves a role in generating signaling complexes in response to tyrosine kinase activation. SHB mediates certain responses in platelet-derived growth factor (PDGF) receptor-, fibroblast growth factor (FGF) receptor-, neural growth factor (NGF) receptor TRKA-, T cell receptor-, interleukin-2 (IL-2) receptor- and focal adhesion kinase- (FAK) signaling. Upstream of SHB in some cells lies the SRC-like FYN-Related Kinase FRK/RAK (also named BSK/IYK or GTK). FRK/RAK and SHB exert similar effects when overexpressed in rat phaeochromocytoma (PC12) and beta-cells, where they both induce PC12 cell differentiation and beta-cell proliferation. Furthermore, beta-cell apoptosis is augmented by these proteins under conditions that cause beta-cell degeneration. The FRK/RAK-SHB responses involve FAK and insulin receptor substrates (IRS) -1 and -2. Besides regulating apoptosis, proliferation and differentiation, SHB is also a component of the T cell receptor (TCR) signaling response. In Jurkat T cells, SHB links several signaling components with the TCR and is thus required for IL-2 production. In endothelial cells, SHB both promotes apoptosis under conditions that are anti-angiogenic, but is also required for proper mitogenicity, spreading and tubular morphogenesis. In embryonic stem cells, dominant-negative SHB (R522K) prevents early cavitation of embryoid bodies and reduces differentiation to cells expressing albumin, amylase, insulin and glucagon, suggesting a role of SHB in development. In summary, SHB is a versatile signal transduction molecule that produces diverse biological responses in different cell types under various conditions. SHB operates downstream of GTK in cells that express this kinase.

Interleukin-2 induces heterodimerization of the IL-2 receptor beta and gamma subunits. This study addresses a role of the Shb adapter protein in IL-2 receptor signaling in T and NK cells. The IL-2Rbeta and gamma chains were found to co-immunoprecipitate with Shb, when each alone was co-expressed with Shb in COS cells. Using fusion proteins, the Shb SH2 domain was found to associate in a phosphotyrosine-dependent manner with the IL-2 receptor beta and gamma subunits upon IL-2 stimulation in primary T cells and the NK cell line NK-92. The main binding site of the Shb SH2 domain was phosphorylated Tyr-510 in the IL-2Rbeta chain. Shb was also phosphorylated upon IL-2 stimulation when overexpressed together with IL-2Rbeta (in pre-B cells, which express the gamma chain constitutively). These cells were also less apoptotic in the presence of IL-2 than cells overexpressing a mutant Shb (with a defect SH2 domain) or cells expressing a mutant IL-2Rbeta, with the Shb binding sites mutated to phenylalanine (Y392F, Y510F). JAK1 and JAK3 were also found to associate with Shb, but in contrast to the Shb-IL-2 receptor association, JAK1 and 3 appear to associate with the proline-rich regions of Shb. In conclusion, Shb links the IL-2 receptor to other signaling proteins and mediates the regulation of apoptosis in the presence of IL-2.

Recent work has implicated the importance of adapter proteins in signal transduction. To identify homologues of the previously identified adapter protein Shb, database searches were performed. A Shb-like protein was found which we have named Shf. Shf contains an SH2 domain and four putative tyrosine phosphorylation sites and is mainly expressed in skeletal muscle, brain, liver, prostate, testis, ovary, small intestine, and colon. The SH2 domain of Shf bound to the PDGF-α-receptor at tyrosine-720, but not to the PDGF-β-receptor in PAE cells. Pervanadate induced tyrosine phosphorylation of Shf in NIH3T3 fibroblasts overexpressing this protein, whereas PDGF-AA alone had no detectable effect. NIH3T3 cells overexpressing Shf displayed significantly lower rates of apoptosis than control cells in the presence of PDGF-AA. Our findings suggest a role for the novel adapter Shf in PDGF-receptor signaling and regulation of apoptosis.