Maintenance of platelet homeostasis by tyrosine phosphatases and vascular heparan sulfates

Introduction

Platelets are highly reactive fragments of megakaryocytes (MKs) that have been implicated in all major pathophysiological processes. However, the molecular mechanisms controlling the number and reactivity of platelets in the circulation remain incompletely defined.

Current Understanding

The prevailing thinking is that mechanical forces are the primary drivers of platelet production. However, this logic is flawed and the evidence is contradictory.

Overlooked Mechanisms

What is glaringly overlooked are intrinsic inhibitory mechanisms and extrinsic cues that provide a break system and directionality to MKs. Central to this model is the concept of an MK/platelet checkpoint and gatekeeper that prevents platelet production in a haphazard manner, which has never been applied to this fundamental physiological process.

Hypothesis

Based on pioneering work from my laboratory, I hypothesize that:

1. Protein-tyrosine phosphatase (PTP)-linked receptors and vascular heparan sulfates (HS) are critical regulators of platelet production.
2. These receptors can be harnessed through the use of synthetic heterobifunctional molecules to regulate the threshold of MK/platelet activation and function in health and disease.

Critical Components

Critical components of this mechanism include:

• The co-inhibitory receptor G6B, which signals via the non-transmembrane PTPs Shp1 and Shp2, is regulated by vascular HSs, and is the primary gatekeeper of the MK/platelet checkpoint.
• The receptor-type PTP CD148, which is regulated by vascular HS proteoglycans and extracellular matrix proteins, and is a master regulator of Src family kinases and the threshold of MK/platelet activation.

Impact of Findings

Findings from this proposal will revolutionize MK/platelet biology and pioneer a novel class of tools and therapeutics for investigating and treating MK/platelet-based pathologies.